Synthesis of chromanol derivatives

ABSTRACT

The present invention relates to a process for the production of chromanol derivatives, more specifically to a process for preparing a compound of the general formula I wherein R1, R2 and R3 independently of each other are selected from hydrogen and methyl, R4 is selected from C-1-C6-alkyl, and X is selected from C1-C20-alkyl and C2-C20-alkenyl.

The present invention relates to a process for the production ofchromanol derivatives, in particular to a process for the production ofcompounds belonging to the vitamin E family.

BACKGROUND OF THE INVENTION

Vitamin E is the most important fat-soluble antioxidant in biologicalsystems. The term vitamin E includes all tocol and tocotrienolderivatives having the biological activity of(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(I.1), which is the most relevant vitamin E for human health (see forinstance W. Bonrath et al., Angew. Chem. Int. ed., 2012, 51,12960-12990; T. Netscher, Vitamins and Hormons, 2007, Elsevier Inc.volume 76, 155).

Naturally occurring vitamin E encompasses the tocopherol compounds offormulae I.1 to I.4 (α-, β-, γ- and δ-tocopherol) as well as thetocotrienol compounds of formulae I.5 to I.8 (α-, β-, γ- andδ-tocotrienol).

These naturally occurring compounds exist in the form of single isomers,i.e. the α-, β-, γ-, and δ-tocopherols (I.1 to I.4) have 2R,4R,8Rconfiguration and the corresponding α-, β-, γ-, and δ-tocotrienols (I.5to I.8) are present as the 2R,3E,7E isomers.

Industrially, α-tocopherol is mainly produced in the form of all racemicα-tocopherol (all-rac-I.1) and all-rac-α-tocopherol acetate (all-racI.1a), which represent equimolar mixtures of all 8 possiblestereoisomers. Typically, all-racemic α-tocopherol is synthesized viathe condensation of trimethylhydroquinone (III.1) with all-racemicisophytol (all-rac-isophytol), as depicted in scheme 1. Thiscondensation reaction involves a Friedel-Crafts alkylation of thetrimethylhydroquinone (III.1) followed by a subsequent ring-closingreaction. The thus obtained all-racemic α-tocopherol (all-rac-I.1) isthen transformed into the more stable acetate form (all-rac-I.1a) viaesterification with acetic acid anhydride.

The other tocopherols, i.e. β-, γ- and δ-tocopherol, as well as thecorresponding tocotrienols, in particular α-tocotrienol, preferably inthe form of their acetates, are generally produced in analogous way.

Over the last decades, a large number of processes for the production ofα-tocopherol have been developed. A key step in many of these processesis the Friedel-Crafts alkylation of the corresponding hydroquinoneprecursors, as depicted in scheme 1, which is performed in the presenceof a Friedel-Crafts catalyst.

Generally, strong Lewis acids such as zinc chloride, aluminium chloride,tin chloride, iron chloride, titanium tetrachloride or borontrifluoroetherate and combinations of strong Lewis acids and strongBrønsted acids, such as hydrochloric acid, sulfuric acid and phosphoricacid, are used as catalysts for this Friedel-Crafts reaction.

WO 9728151 for example describes the reaction of2,3,5-trimethylhydroquinone with isophytol to α-tocopherol in thepresence of cyclic carbonate solvents by using homogeneous Brønstedacids and Lewis acids, such as orthoboric acid, oxalic acid, tartaricacid, citric acid or boron trifluoroetherate at elevated reactiontemperatures in the range of from 145 to 155° C.

However, the use of these catalysts is associated with severaldisadvantages. First of all, they can foster the formation ofby-products (e.g. the use of oxalic acid, tartaric acid or citric acidgenerally increases the formation of unwanted phytadienes). Furthermore,these catalysts can typically not be recovered and reused, because oftheir instability towards water. Furthermore, the catalysts are used instoichiometric amounts or in a high catalytic loading. Besides, thesecatalysts are typically corrosive and waste containing heavy metals,such as zinc or tin, and chloride are often obtained.

In order to circumvent these disadvantages, heterogeneous catalysts havebeen applied as catalyst for the Friedel-Crafts alkylation.

Odinokov et al., ARKIVOC 2003, (xiii), 101-118 and Scegolev et al., UDK:547.814.I.07 1982, VINITI 7.09.82, No. 4780-82, for example, describethe use of zeolite catalysts, such as Tseokar-10 or ASNC-ZP in thereaction of hydroquinones with tertiary isoprenoid allylic alcohols. Theuse of zeolites has the disadvantage, that the reactions have to beperformed at high dilutions and that these zeolites are often notcommercial available.

Y. Tachibana, Bull. Chem. Soc. Japan, 1977, 50 (9), 2477, describes theuse of zinc chloride or tin chloride treated strongly acidicion-exchanged resins, such as amberlyst 15, as catalyst in the reactionof trimethylhydroquinone with isophytol. However, these catalyststypically suffer from a low catalytic activity and wastes containingheavy metals and chloride are produced.

EP 677520 A1 and Matsui et al., Bull. Chem. Soc. Japan, 1996, 69, 137,describe the use of ion-exchanged bentonite, montmorillonite or saponitethrough treatment with scandium chloride or other metal salts, such asyttrium, lanthanum, etc., as catalyst for the reaction oftrimethylhydroquinone with isophytol has the disadvantage that largeamounts of catalyst are required.

DE 2404621 describes a process for the preparation of α-tocopherol byreacting trimethylhydroquinone with phytol, isophytol or a derivativethereof using a solid acid catalyst having a specific acid strength.Among others, naturally occurring minerals, which exhibit acidity, suchas acid clay, bentonite, kaolin or mordenite, are mentioned as suitablecatalysts. In a specific example, bentonite is used as the catalystyielding the desired α-tocopherol in 51.8% yield. Also here, largeamounts of the catalyst are required and the obtained yields aremoderate.

SUMMARY OF THE INVENTION

It is, thus, an object of the present invention to provide a process forthe production of chromanol derivatives, in particular to provide aprocess for the production of compounds belonging the vitamin E familyin esterified form, which is efficient and which provides the desiredproducts in high yield and selectivity, without the need to applyexpensive, corrosive and/or environmentally harmful catalysts andsolvents. In particular, the formation of undesired by-products shouldbe reduced to avoid laborious purification procedures. The processshould be simple and applicable in large-scale production. Besides, therequired amounts of catalyst should be in the sub-stoichiometric rangeand the applied catalyst should be recyclable.

It was now surprisingly found that these and further objects areachieved by a process, which comprises the Friedel-Crafts alkylation ofthe corresponding hydroquinone precursors followed by the esterificationof the thus obtained condensation product, where both of these steps areperformed in the presence of a bentonite catalyst.

Accordingly, the present invention relates to a process for preparing acompound of the general formula I

wherein

-   R¹, R² and R³ independently of each other are selected from hydrogen    and methyl,-   R⁴ is selected from C₁-C₆-alkyl, and-   X is selected from C₁-C₂₀-alkyl and C₂-C₂₀-alkenyl,

comprising the following steps:

-   a) providing a hydroquinone compound of the general formula II,

-   -   wherein R¹, R² and R³ are as defined above,

-   b) reacting the hydroquinone compound II provided in step a) with an    unsaturated compound of the general formula III.a or III.b

-   -   wherein    -   X is as defined above,    -   Y is selected from OH, halogen, —O—R¹¹, —S—R¹² and —SO₂—R¹²,    -   R¹¹ is selected from C₁-C₄-alkyl, C₁-C₄-alkanoyl and        trifluoroacetyl, and    -   R¹² is selected from C₁-C₆-alkyl, trifluoromethyl and phenyl,        where phenyl is unsubstituted or substituted with 1, 2, 3, 4 or        5 radicals selected from halogen and methyl,    -   in the presence of a bentonite catalyst, and

-   c) reacting the condensation product obtained in step b) with a    C₂-C₇-carboxylic acid or with a C₂-C₇-carboxylic acid anhydride in    the presence of a bentonite catalyst.

DETAILED DESCRIPTION OF THE INVENTION

In the context of the present invention, the term “alkyl” as used hereinrefers to a linear or branched saturated hydrocarbon radical having 1 to3 (“C₁-C₃-alkyl”), 1 to 4 (“C₁-C₄-alkyl”), 1 to 6 (“C₁-C₆-alkyl”) or 1to 20 (“C₁-C₂₀-alkyl”) carbon atoms. C₁-C₃-Alkyl is methyl, ethyl,propyl and isopropyl. C₁-C₄-Alkyl is additionally n-butyl,1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or1,1-dimethylethyl (tert-butyl). C₁-C₆-Alkyl is additionally also, forexample, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl or 1,3-dimethylbutyl. C₁-C₂₀-Alkyl isadditionally also, for example, n-heptyl, 1-methylhexyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,4-dimethylpentyl,n-octyl, isooctyl, 2-ethylhexyl, n-nonyl, isononyl, n-decyl, iso-decyl,2-propylheptyl, n-undecyl, isoundecyl, 2,4-dimethylnonyl, n-dodecyl,isododecyl, n-tridecyl, isotridecyl, tetradecyl, isotetradecyl,hexadecyl, isohexadecyl, 4,8,12-trimethyltridecyl, octadecyl,isooctadecyl and the like.

In the context of the present invention, the term “C₁-C₄-alkanoyl”denotes a C₁-C₄-alkyl group, as defined above, attached via a carbonyl[(C═O)] group to the remainder of the molecule. The term“C₁-C₆-alkanoyl” denotes a C₁-C₆-alkyl group, as defined above, attachedvia a carbonyl [(C═O)] group to the remainder of the molecule.C₁-C₄-alkanoyl is methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,isopropylcarbonyl, n-butylcarbonyl, 1-methylpropylcarbonyl,2-methylpropylcarbonyl or 1,1-dimethylethylcarbonyl. C₁-C₆-alkanoyl isadditionally, for example, n-pentylcarbonyl, 1-methylbutylcarbonyl,2-methylbutylcarbonyl, 3-methylbutylcarbonyl,1,2-dimethylpropylcarbonyl, n-hexyl-carbonyl, 1-methylpentylcarbonyl,2-methylpentylcarbonyl, 3-methylpentylcarbonyl, 4-methylpentylcarbonylor 1,3-dimethylbutylcarbonyl.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine, in particular fluorine, chlorine or bromine. Halogen as asubstituent on phenyl is preferably Cl or Br.

The compounds obtainable by the process of the present invention arecompounds of the general formula (I)

wherein

-   R¹, R² and R³ independently of each other are selected from hydrogen    and methyl,-   R⁴ is selected from C₁-C₆-alkyl, and-   X is selected from C₁-C₂₀-alkyl and C₂-C₂₀-alkenyl.

Due to their structure, the compounds (I) can be present in the form ofpure enantiomers or diastereoisomers as well as in the form ofenantiomer or diastereoisomer mixtures.

The term “stereoisomers” encompasses optical isomers, such asenantiomers or diastereoisomers, the latter existing due to more thanone stereogenic centre in the molecule. The compounds of the formula(I), where X is not methyl, have at least one stereogenic centre, namelythe carbon atom in the 2-position of the chromane ring. Furthermore, incompounds (I) the radical X may also have at least one stereogeniccentre, for example if X is selected from 4,8-dimethylnonyl or4,8,12-trimethyltridecyl. The invention relates to both, the pureenantiomers or diastereoisomers of compounds (I) as well as to mixturesthereof.

Furthermore, in case the radical X is selected C₂-C₂₀-alkenyl, compounds(I) may also have at least one double bond, which can have E- orZ-configuration, for example if X represents the isoprenyl moieties4,8-dimethyl-3,7-nonadienyl or 4,8,12-trimethyl-3,7,11-tridecatrienyl.Thus, the invention also relates to compounds (I), wherein the doublebond(s), if present, has/have pure E- or Z-configuration and/or is/arepresent as E/Z-mixture(s).

Preferably, in compounds (I) and (II) of the process of the presentinvention, the radicals R¹, R² and R³ have the following meanings:

-   R¹ is methyl,-   R² is methyl, and-   R³ is methyl,-   or-   R¹ is methyl,-   R² is hydrogen, and-   R³ is methyl,-   or-   R¹ is hydrogen,-   R² is methyl and-   R³ is methyl,-   or-   R¹ is hydrogen,-   R² is hydrogen, and-   R³ is methyl.

In particular, in compounds (I) and (II), the radicals R¹, R² and R³ aremethyl.

Preferably, in compounds (I) of the process of the present invention,the radical R⁴ is C₁-C₄-alkyl, more preferably C₁-C₂-alkyl, inparticular ethyl.

Preferably, in compounds (I), (III.a) and (III.b) of the process of thepresent invention, the moiety X is selected from methyl or has one ofthe following meanings X-1 to X-6

wherein * indicates the attachment point to the chromane ring.

In particular, in compounds (I), (III.a) and (III.b) of this firstembodiment, the moiety X is selected from (X-3) or (X-6)

wherein * indicates the attachment point to the rest of the molecule.

In a preferred embodiment, in compounds (I)

-   R¹ is methyl,-   R² is methyl, and-   R³ is methyl,-   or-   R¹ is methyl,-   R² is hydrogen, and-   R³ is methyl,-   or-   R¹ is hydrogen,-   R² is methyl and-   R³ is methyl,-   or-   R¹ is hydrogen,-   R² is hydrogen, and-   R³ is methyl,-   R⁴ is C₁-C₄-alkyl, and-   X is selected from methyl or a radical of formulae X-1 to X-6.-   In a more preferred embodiment, in compounds (I)-   R¹ is methyl,-   R² is methyl, and-   R³ is methyl,-   or-   R¹ is methyl,-   R² is hydrogen, and-   R³ is methyl,-   or-   R¹ is hydrogen,-   R² is methyl and-   R³ is methyl,-   or-   R¹ is hydrogen,-   R² is hydrogen, and-   R³ is methyl,-   R⁴ is C₁-C₂-alkyl, in particular ethyl, and-   X is methyl or has one of the following meanings (X-3) or (X-6)

-   -   wherein * indicates the attachment point to the rest of the        molecule.

In a particular embodiment, in compounds (I)

-   R¹, R² and R³ are methyl,-   R⁴ is ethyl, and-   X has one of the following meanings (X-3) or (X-6)

-   -   wherein * indicates the attachment point to the rest of the        molecule.

Preferably, in compounds (III.a) and (III.b), the radical Y is selectedfrom OH, Cl, Br,

-   I, —O—R¹¹, —S—R¹² and —SO₂—R¹², wherein-   R¹¹ is selected from C₁-C₄-alkanoyl and trifluoroacetyl, and-   R¹² is selected from C₁-C₃-alkyl, trifluoromethyl, phenyl,    4-methylphenyl and pentafluorophenyl.

More preferably, in compounds (III.a) and (III.b), the radical Y isselected from OH, Br, —O—R¹¹, —S—R¹² and —SO₂—R¹², wherein

-   R¹¹ is selected from acetyl and trifluoroacetyl, and-   R¹² is selected from methyl, trifluoromethyl and 4-methylphenyl.

In particular, in compounds (III.a) and (III.b), the radical Y isselected from OH, —O—R¹¹ and —SO₂—R¹², wherein

-   R¹¹ is selected from acetyl, and-   R¹² is selected from methyl, trifluoromethyl and 4-methylphenyl.

Step a

Step a) of the present invention comprises the provision of ahydroquinone compound of the general formula (II).

These hydroquinone compounds are either commercially available or can beprepared from readily available precursors by processes described in theart.

The hydroquinone compounds of the general formula (II) can for examplebe prepared by reduction of the corresponding benzoquinone derivativesof the general formula (IV) as depicted in Scheme 2.

The reduction step i) is typically carried out with chemical reducingmeans. A suitable chemical reducing means is for example a metal incombination with an acid. Metals that will react with acids to formhydrogen are employed. Typical metals of this type are zinc, iron,magnesium, aluminium, calcium, manganese, cadmium, and the like. Themost preferred metals are zinc and iron. Suitable acids are those, whichhave sufficient acidity to react with the metal employed. Preferredacids are mineral acids, such as hydrochloric acid, sulphuric acid,phosphoric acid, and the like. The most preferred acid is hydrochloricacid. When hydrochloric acid is employed in the reducing step, excellentyields of hydroquinone are obtained.

As alternative means, metal hydrides, such as sodium hydride, sodiumaluminium hydride, sodium borohydride, and the like, can be employed.

A further reducing means that can advantageously be used in thereduction step i) is catalytic hydrogenation. In this variant, thebenzoquinone is usually dissolved in an inert solvent and contacted withhydrogen and a hydrogenation catalyst. In conducting this reduction, anysolvents that are inert, i.e. any solvents that do not react with thestarting materials, intermediates and reagents applied in the reductionor with the obtained products, can be employed. Suitable solvents arefor example alcohols, such as methanol, ethanol, propanol andisopropanol; aromatic and substituted aromatic hydrocarbons, such asbenzene, chlorobenzene, dichlorobenzenes, toluene, xylene; and aliphatichydrocarbons, such as pentane, hexanes, cyclohexane, heptanes, octanes,nonanes, decanes, ligroin and petrol ether, halogenated aliphatichydrocarbons, such as dichloromethane, trichloromethane andtetrachloromethane, ethers, such as dibutyl ether, THF, 1,4-dioxane,1,2-dimethoxyethane; as well as mixtures thereof.

Suitable hydrogenation catalysts are those commonly used in the art tocatalyse the hydrogenation of organic compounds. Some examples of theseinclude palladium chloride on charcoal, activated nickel, nickel-nickeloxide, platinum-platinum oxide, platinum on charcoal, copper chromite,Raney nickel, palladium, platinum black, palladium sponge, nickel,copper impregnated alumina, palladium black, activated alumina, Raneycopper, chromium, vanadium, molybdenum, and the like. Especiallysuitable hydrogenation catalysts that can be used in the reduction stepi) are platinum, palladium, Raney nickel, copper impregnated alumina andcopper chromite.

The catalytic hydrogenation may be carried out at atmospheric pressureor at elevated pressures. Higher pressures usually result in fasterhydrogenation rates. Extremely high pressures are not required becausethe benzoquinones are readily reduced.

Suitable hydrogenation pressures are typically in the range of from 1 to50 bar.

The hydrogenation is carried out at a temperature high enough to promotethe reduction of the benzoquinone, but not so high as to causedegradation of the reactants, reaction medium or products. The suitablereaction temperature is typically in the range of from 20 to 150° C.

In a preferred embodiment of the present invention, the provision of thehydroquinone compound II in step a) comprises the following steps:

-   a.1) providing a quinone compound of the general formula IV,

-   -   wherein R¹, R² and R³, independently of each other, are hydrogen        or methyl,

-   a.2) catalytic hydrogenation of the quinone compound of formula IV    provided in step a.1) in the presence of hydrogen and a    hydrogenation catalyst.

Hydrogenation catalysts that can be used in the catalytic hydrogenationin step a.2) are those commonly used in the art to catalyse thehydrogenation of organic compounds.

Some examples of these include palladium chloride on charcoal, activatednickel, nickel-nickel oxide, platinum-platinum oxide, platinum black,platinum on charcoal, copper chromite, Raney nickel, palladium,palladium black, palladium on charcoal, palladium sponge, nickel, copperimpregnated alumina, activated alumina, Raney copper, chromium,vanadium, molybdenum, and the like.

Preferably the hydrogenation catalyst applied in step a.2) is aheterogeneous hydrogenation catalyst, more preferably a supported metalcatalyst.

Suitable supports are for example carbon, carbon black, active charcoal,graphite, aluminium oxide, silicon oxide, titanium dioxide, zirconiumdioxide, cerium dioxide, lanthanium(III)-oxide, zinc oxide, silicates,asbestos, silicon carbide, calcium carbonate, magnesium carbonate,magnesium sulfate, barium carbonate, barium sulfate, zeolites,diatomaceous earth, and mixtures thereof.

Even more preferably, the hydrogenation catalyst applied in step a.2) isa carbon supported catalyst. In particular, the hydrogenation catalystapplied in step a.2) is a carbon supported noble metal catalyst, i.e. anoble metal catalyst comprising a support material based on carbon (C),for example activated carbon.

In principle, suitable carbon-based support materials are all carbonmaterials known to the person skilled in the art for such uses. Suitablecarbon-based support materials are for example carbon, carbon black,active charcoal and graphite. The support materials may preferably beused in the form of shaped bodies, granules, strands, pellets, spall,tablets or prills. The BET surface area of the support materials (25°C.) is typically in the range from 1 to 10 000, preferably from 10 to5000, m²/g, but is uncritical in most cases for the process of theinvention.

Suitable noble metals are for example selected from Pt, Pd, Ru, Rh andIr.

Specifically, the hydrogenation catalyst applied in step a.2) isselected from a carbon supported Pd catalyst, more specifically from Pdon charcoal.

The metal content of the supported metal catalyst is typically in therange of from 0.1% to 20% by weight, preferably in the range of from 1%to 15% by weight, based on the total weight of the carbon supportednoble metal catalyst.

Typically, the amount of the hydrogenation catalyst used in step a.2) ofthe present invention is in the range of from 0.05% to 20% by weight,preferably in the range of from 0.1% to 10% by weight, more preferablyin the range of from 0.2% to 5% by weight, based on the amount ofquinone present in the reaction mixture.

The catalytic hydrogenation may be carried out at atmospheric pressureor at elevated pressures. Higher pressures usually result in fasterhydrogenation rates. Extremely high pressures are not required becausethe benzoquinones are readily reduced. The catalytic hydrogenation instep a.2) is typically performed at a pressure in the range from 1 to100 bar, preferably in the range from 1 to 50 bar, especially in therange from 2 to 30 bar.

The hydrogenation is carried out at a temperature high enough to promotethe reduction of the benzoquinone, but not so high as to causedegradation of the reactants, reaction medium or products. In thispreferred embodiment, the suitable reaction temperature is typically inthe range of from 20 to 150° C., preferably in the range from 30 to 120°C. and especially in the range from 40 to 100° C.

The quinone compounds (IV) provided in step a.1) are either commerciallyavailable or can be prepared from readily available precursors byprocesses described in the art.

For example, 2,3,5-trimethylquinone can be prepared by catalyticmethylation of m-cresol to 2,3,6-trimethylphenol (step ii), followed byoxidation of the thus obtained 2,3,6-trimethylphenol using an oxidationagent (step iii)),as depicted in scheme 3

The catalytic methylation in step ii) is typically carried out withmethanol or dimethylether as the alkylating agent in the presence of ametal oxide catalyst, such as for example aluminium oxide, siliconoxide, magnesium oxide, calcium oxide, barium oxide, iron oxide,chromium oxide, zinc oxide, manganese oxide, zirconium oxide, thoriumoxide, and the like, as well as mixed metal oxide catalysts.

The individual reaction conditions for the catalytic methylation ofphenols, such as m-cresol, are well known to the skilled person.

The oxidation in step iii) can be conducted according to standardprocedures that are well known to the skilled person. Typically, theoxidation is carried out in the presence of an oxidizing agent,optionally with the help of a metal salt or noble metal catalyst. Inprinciple, all oxidizing agents known to the skilled person to becapable to oxidize phenols to quinones can be used in the oxidation instep ii).

Suitable oxidizing agents are for example:

-   -   hydrogen-peroxide, oxygen or an oxygen containing gas in the        presence of catalytic amounts of metal salt, such as Mg(II)-,        Ca(II)-, Ba(II)-, Cu(II)-, Fe(II)-, Cr(II)-, Mn(II)-, Co(II)-,        Ni(II)-, Zn(II)-, sulfates or chlorides, as well as mixtures of        these metal salts, or a noble metal catalyst, such as for        example a ruthenium, rhodium, platinum or palladium catalyst;    -   mineral acids, such as nitric acid, sulfuric acid, chloric acid,        hypochloric acid, perchloric acid, iodic acid or periodic acid;        or    -   organic peroxy acids, such as perbenzoic acid or        meta-chloroperbenzoic acid.

Suitable reaction conditions for this oxidation reaction are well knownto the skilled person.

In a more preferred embodiment of the present invention, the catalytichydrogenation reaction in step a.2) is carried out in the presence of acarbonate solvent selected from organic carbonates.

Preferably, the carbonate solvent is selected from cyclic and linearcarbonates of the general formula V.a and V.b

wherein

R¹⁵, R¹⁶ and R¹⁷ independently of each other are selected from hydrogen,methyl and ethyl, in particular from hydrogen and methyl,

R¹⁸ is selected from hydrogen, phenyl and C₁-C₁₅-alkyl, whereC₁-C₁₅-alkyl is unsubstituted or substituted with 1, 2, or 3 radicals,selected from C₁-C₃-alkoxy, polyalkyleneoxide, phenyl and phenoxy, inparticular from hydrogen, phenyl, C₁-C₃-alkyl and benzyl, and

R¹⁹ independently of each other are selected from C₁-C₄-alkyl, inparticular from ethyl and n-propyl.

More preferably, the carbonate solvent is selected from cyclic andlinear carbonates of the general formula V.a and V.b

wherein

R¹⁵, R¹⁶ and R¹⁷ independently of each other are selected from hydrogenand methyl,

R¹⁸ is selected from hydrogen, methyl, ethyl, phenyl and benzyl, and

R¹⁹ independently of each other are selected from ethyl and n-propyl.

Amongst these carbonate solvents, those carbonate solvents are preferredwhich have a boiling point of at least 100° C., more preferably of atleast 120° C., in particular of at least 140° C.

Specifically, the carbonate solvent is selected from ethylene carbonate,propylene carbonate, butylene carbonate, 2,3-propylene carbonate,isobutylene carbonate, diethyl carbonate and di-n-propyl carbonate.

These cyclic and acyclic carbonates do not give rise to anytoxicological concerns, which is very important for the preparation ofthe compounds of the general formulae I and II. Furthermore, thesesolvents are well biodegradable.

In this more preferred embodiment of the present invention, thecatalytic hydrogenation in step a.2) may additionally be conducted inthe presence of an apolar hydrocarbon solvent (HS).

Accordingly, in an alternative embodiment of the present invention, thecatalytic hydrogenation in step a.2) is carried out in a solvent mixtureconsisting of at least one carbonate solvent, as defined above, and atleast one apolar hydrocarbon solvent (HS).

Preferably, the apolar hydrocarbon solvent (HS), if present, is selectedfrom the following groups:

-   HS.1 linear and branched alkanes having 5 to 15 carbon atoms, such    as for example pentane, hexanes, heptanes, octanes, nonanes,    decanes, ligroin and petrol ether;-   HS.2 cycloalkanes having 5 to 10 carbon atoms, such as for example    cyclohexane;-   HS.3 aromatic hydrocarbons having 6 to 12 carbon atoms, such as for    example benzene, toluene, xylenes, ethylbenzene and tetralin;

and mixtures thereof.

More preferably, the apolar hydrocarbon solvent (HS) is selected fromthe groups HS.1 and HS.2.

Specifically, the apolar hydrocarbon solvent (HS) is selected fromhexane, cyclohexane, heptane, octane and nonane, more specifically fromheptane and octane.

In this alternative embodiment, the content of the carbonate solvent inthis solvent mixture is typically in the range of from 35 to 99% byweight, preferably in the range of from 50 to 99% by weight, inparticular in the range of from 50 to 90% by weight, based on the totalweight of the solvent mixture.

Accordingly, the weight ratio of the carbonate solvent to HS applied instep a.2) is typically in the range of from 1:3 to 100:1, preferably inthe range of from 1:1 to 100:1, in particular in the range of from 1:1to 10:1.

In this alternative embodiment, carbonate solvents are preferred, whichare not or only sparingly miscible with the at least one apolarhydrocarbon solvent (HS), which means that step a.2) is carried out in abiphasic solvent mixture consisting of a carbonate solvent-phase and aHS-phase. In this connection, the term “sparingly miscible” means thatless than 5% by weight, preferably less than 2% by weight, morepreferably less than 1% by weight, in particular less than 0.5% byweight, of the polar aprotic solvent (PS) is present in the HS-phase.

In this alternative embodiment, solvent mixtures are preferredconsisting of at least one carbonate solvent and at least one apolarhydrocarbon solvent of the group HS.1.

In particular, in this alternative embodiment, the solvent mixtureconsists of at least one carbonate solvent, selected from ethylenecarbonate, propylene carbonate, butylene carbonate, 2,3-propylenecarbonate, isobutylene carbonate, diethyl carbonate and di-n-propylcarbonate, and at least one apolar hydrocarbon solvent (HS), selectedfrom heptane and octane.

In a specific embodiment of the present invention, step b) is carriedout in at least one carbonate solvent (PS), as defined above.

The catalytic hydrogenation can be carried out in a variety of reactorsknown for this purpose, such as a serial loop reactor as described inU.S. Pat. No. 5,756,856, but also in simpler reactors, as described forexample in DE 2008128. Preference is given to fixed bed reactors, inparticular to trickle bed reactors.

The reaction product, i.e. the compound of formula (II), obtained instep a.2) is typically worked-up by filtering off the hydrogenationcatalyst. The thus obtained reaction mixture can directly be used instep b) of the instant process.

If desired, the thus obtained reaction mixture can be further worked-upin a conventional way, e.g. by mixing with water, separating the phasesand, where appropriate, purifying the crude products by usingchromatographic methods, by distillation, or by recrystallization.

In a preferred embodiment of the present invention, the reaction mixtureobtained in step a.2) is used directly in the reaction in step b) of theinstant process, after removal of the hydrogenation catalyst.

Step b):

Step b) of the present invention comprises the reaction of the compound(II) provided in step a) with an unsaturated compound of the generalformula (III.a) or (III.b)

wherein

X has one of the meanings given above,

Y is selected from OH, halogen, —O—R¹¹, —S—R¹² and —SO₂—R¹²,

R¹¹ is selected from C₁-C₄-alkyl, C₁-C₄-alkanoyl and trifluoroacetyl,and

R¹² is selected from C₁-C₆-alkyl, trifluoromethyl and phenyl, wherephenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 radicalsselected from halogen and methyl,

in the presence of a bentonite catalyst.

Bentonite is formed of highly colloidal and plastic clay. Bentonite isoften used as a thickener and filler for paints, as an additive forceramics and also for health products (e.g. cosmetics, nutrition orpharmaceuticals). Bentonites are good adsorbents and are characterizedby high cation exchange capacity, strong swelling capacity and lowpermeability.

The term “bentonite” or “bentonite catalyst”, as used herein, cangenerally comprise all types of silicate clay minerals containing theelements H, C, O, Si, Al, Mg, Ca, Li, Na, K, Fe, Zn, S, F and allcombinations thereof. For example, the “bentonite” or “bentonitecatalyst” can comprise pyrophyllite, talc, micas (e.g. muscovite,paragonite, phlogopite, biotite, lepidolite, zinnwaldite, taeniolite,fluor-tetrasilicic mica), brittle micas (margarite, chloritoid,seyberite, clintonite), hydrous micas, illites, chlorites, vermiculites,smectites (montmorillonite, saponite, nontronite, beidellite, sauconite,hectorite, fluorhectorite), kandites, serpentines and/or palygorskites(attapulgite, sepiolite). Preferably, the “bentonite” or “bentonitecatalyst” comprises montmorillonites as are described, for example, inKlockmann's textbook of mineralogy, 16th edition, F. Euke Verlag 1978,pages 739-765 and in R. M. Barrer Zeolites and Clay Minerals as Sorbentsand Molecular Sieves, Academic Press, and in Y. Izumi, K. Urabe, M.Onaka Zeolite, Clay, and Heteropoly Acid in Organic Reactions, VCH.

Typically, the main component of bentonite is montmorillonite, a claymineral of the smectite group. Montmorillonite consists of two layers ofsilicon tetrahedrons with a central layer of one aluminium octahedronbetween them. It has hydroxyl groups between the layers as well as onthe surface.

In principle, all deposits containing montmorillonite, as for examplelisted in the monograph “The Economics of Bentonite”, 8th Edition 1997,Roskill Information Services Ltd, London, can be considered as suitablesource of bentonites. Depending on their origin, bentonites may contain,besides montmorillonite, different amounts of a variety of accompanyingminerals, as defined above, and non-mineral components. Suchaccompanying minerals and non-mineral components are in particularquartz, feldspar, kaolin, muscovite, zeolites, titanium oxides, ironoxides, illites, mica calcite and/or gypsum. Preferred raw materials arethose with a high montmorillonite content and a correspondingly lowcontent of secondary components, since the amount of puremontmorillonite in the bentonite determines its performance. The higherthe contents of the montmorillonite in the bentonite, the better will beits performance as an industrial raw material. The montmorillonitecontent can be determined, for example, by methylene blue adsorption.

Preferred raw materials have a methylene blue value of at least 250mg/g, preferably at least 290 mg/g, in particular at least 320 mg/g.Particularly preferred raw materials are those whose exchangeablecations consist to a high percentage of alkali metals, in particularsodium. In terms of charge equivalents, these raw materials contain atleast 25%, preferably at least 40%, of monovalent exchangeable cations.These sodium bentonites raw materials are found in nature, known sourcesfor bentonites containing sodium are e.g. in Wyoming/USA or in India,they are also known by their origin as “Western Bentonites”, “Wyomingbentonites” or by their properties as “swelling Benonites”. Bentoniteswith a high proportion of alkaline earth cations, especially calcium,are known as “Subbentonites” or “Southern Bentonites” and can beconverted to sodium-containing bentonites by alkaline activation.

Finally, it is in principal also possible to produce suitable syntheticclay minerals e.g. by pillaring with organic or metal complex cations(PILCs) and use them for the current invention (M. M. Herling et al. Z.Anorg. Allg. Chem. 2014, 640, 3-4. 547-560; G. Poncelet and J. J.Fripiat Handbook of Heterogeneous Catalysis (2^(nd) Edition) 2008, 1,219-247).

Clay minerals of natural origin may, in addition to the mineralimpurities, also contain non-mineral impurities, especially carboncompounds. Preferred raw materials are bentonites with a total carboncontent of less than 3 wt. %, preferably less than 1 wt. %, particularlypreferably less than 0.5 wt. %.

It is well known that the macroscopic properties and applicability ofbentonites are closely related to the amount and quality of themontmorillonite contained therein, to their pH-value (residual acidity),particle size and their porous microstructure (e.g. surface area,porosity).

Bentonites can be divided into natural bentonites, i.e untreatedbentonites, and treated bentonites (see for example J. Nones et al.,Applied Clay Science, 2015, 105-106, 225-230). In a preferred embodimentof the present invention, the reaction in step b) is carried out in thepresence of a treated bentonite catalyst.

The term “treated bentonite”, as used herein, refers to bentonites,where the structure, texture and other properties of the bentonite aremodified by chemical treatment and/or heat treatment. Thus, theexpression “treated” refers to a chemical treatment and/or heattreatment and the term “treated bentonite”, as used herein, refers tochemically treated and/or heat treatment bentonite. Generally, thechemical treatment of the bentonite catalyst comprises acid treatment,alkaline treatment, metal salt treatment (cation exchange) or organictreatment. The bentonites obtained by an acid treatment or alkalinetreatment are also called “activated bentonites” (acid activatedbentonites or alkaline activated bentonites).

Preferably the chemical treatment of the bentonite catalyst comprisesmetal salt treatment (cation exchange) or an acid treatment.

In a more preferred embodiment of the present invention, the reaction instep b) is carried out in the presence of an acid treated bentonitecatalyst.

The term “acid treated bentonite” or “acid activated bentonites”, asused herein, refers to bentonites, which are treated with a Brønstedacid, e.g. a mineral acid, such as HCl or H₂SO₄, H₃PO₃, HNO₃, boricacid, silicic acid, carboxylic acids, such as formic acid or aceticacid, or other organic acids, such as trifluoroacetic acid, methanesulfonic acid, toluene sulfonic acid or trifluoromethane sulfonic acid.Preference is given to HCl and/or H₂SO₄ or mixtures of HCl and/or H₂SO₄with other inorganic or organic acids. Typically, acid-activatedbentonites are used on a large scale as bleaching earths for thediscoloration of oils.

The treatment with mineral acid is also known to impart surface acidityof the clay, which improves its catalytic properties (P. Komandel,Applied Clay Science, 2016, 131, 84-99; D. A. D'Amico et al. AppliedClay Science, 2014, 99, 254-260). Without being bound to theory, it isbelieved that during acid treatment or acid activation, respectively,the edges of the silicate sheets of the clay minerals in the bentoniteare opened and the Al³⁺ and Mg²⁺ cations of the octahedral sheet becomesoluble. The chemistry of this activation process, where an acidichydrogen ion, e.g. an acidic hydrogen ion from sulfuric acid, opens thesheet structure of the clay minerals in the bentonite and forms acidsites, is for example illustrated in J. Amorim et al. HydrocarbonEngineering 2016, 21, 11, 83-8. The final acid treated bentonitescontain amorphous, porous, protonated and hydrated silica with athree-dimensional cross-linked structure (P. Komandel Applied ClayScience, 2016, 131, 84-99).

Processes for the production of acid-activated clay minerals, inparticular layered silicates, such as bentonites, are well known in theart; an overview is for example provided by EP0398636 (B1) and adetailed process for the acid activation of clay minerals, such asbentonites, can for example be found in DE10245198 (A1).

Alkaline treatment of bentonites relates to a treatment of thebentonites with mineral bases, such as NaOH, KOH or sodium carbonate, ororganic bases, such as ammonia, trimethylamine or tetraalkylammoniumhydroxides. Alkaline activation is typically performed by treatment withsodium carbonate.

The organic treatment of bentonites relates to a treatment of thebentonites with organic compounds, such as quaternary ammonium cations(e.g. alkylammonium and α-ω-dialkylammonium).

Further organic and inorganic compounds that are exchanged into theabove described minerals include: hydrazine, urea, formamide, acetamide,the Li, Na, K, Rb, Cs and NH₄ salts of lower fatty acids (acetates,propionates, cyanoacetates), oxalate, glycollate, alaninate, lysinate,lactate, glycerine, acetylacetone, a-methoxyacetyl-acetone,acetoaceticethylester, nonanetrione-2:5:8,hexanedione-2:5,β:β′-oxydipropio-nitrile, p-ethoxypropionitril,tetracyanoethylene, 7,7,8,8-tetracyanoquinomethane,bis-(2-ethoxyethyl)-ether, bis-(2-methoxyethyl)-ether,ethyleneglycoldiglycid ether, triethyleneglycol, diethyleneglycol,triethyleneglycoldiacetate, diethylenegylcoldiacetate, hexandiol-1:6,pentanediol-1:5, 2:4-hexadiynediol-1:6.

Further organic bases that are exchanged into the above describedminerals are amines like n-propylamine, n-butylamine, n-hexylamine,n-octylamine, benzidine, N,N,N′,N′-tetramethylbenzidine, diethylamine,triethylamine, triphenylamine, p-phenylenediamine,N,N′-dimethyl-p-phenylenediamine,N,N,N′,N′-tetramethyl-p-phenylenediamine, trans-4,4′-diaminostilbenedihydrochloride, benzylamine, aniline, o-toluidine.

Further long-chain alkylammonium salts that are exchanged into the abovedescribed minerals are 1-n-alkyl pyridinium bromides and cetyltrimethylammonium bromide.

Furthermore, glycine and its peptides, a variety of other amino-acidsand ligands that are exchanged into the above described minerals aredescribed in R. M. Barrer Zeolites and Clay Minerals as Sorbents andMolecular Sieves, Academic Press and references cited therein.

Preferably, the “acid treated bentonite catalyst” is selected frombentonites treated with mineral acids as well as from bentonites treatedwith strong organic acids. In particular, the “treated bentonitecatalyst” is selected from bentonites treated with mineral acids.

These bentonite catalysts do not cause corrosion problems for thereaction apparatus or a contamination of waste water with metal ions orinorganic acids and are sufficiently acidic to carry out the reaction instep b) in reasonable to high reaction rates.

Acid treated bentonites are either commercially available or they can beprepared using processes that are well described in the art, asillustrated above.

Commercially available acid treated bentonites (e.g also known as acidleached bentonites having the CAS-No. 70131-50-9) that can be applied ascatalysts in the reaction in step b) are for example:

-   -   montmorillonite K 10, montmorillonite K 30, montmorillonite        (Aluminum pillared clay) (CAS 139264-88-3), montmorillonite-KSF        (CAS 1318-93-0), obtainable e.g. from Sigma-Aldrich;    -   TONSIL™ catalysts from the company Clariant Produkte        (Deutschland) GmbH.

Typically, the bentonite catalyst applied in step b) of the instantprocess has a BET surface area in the range of from 50 to 800 m²/g,preferably in the range of from 100 to 600 m²/g, more preferably in therange of from 120 to 500 m²/g, in particular in the range of from 150 to400 m²/g. The expression “BET surface area”, as used herein, refers tothe well-known Brunauer-Emmett-Teller method of determining surfacearea. The BET surface area values given in the present application aredetermined via nitrogen adsorption by the BET method by largelyfollowing DIN 66131 (1973), as described in detail below.

Typically, the bentonite catalyst applied in step b) of the instantprocess has a residual acidity, measured as mg KOH/g bentonite bytitration with potentiometric indication, in the range of from 3 to 70,preferably in the range of from 5 to 50, more preferably in the range offrom 10 to 45, in particular in the range of from 15 to 40. The residualacidity (mg KOH/g bentonite) is determined by following standardprocedures, as described in the experimental section below.

In brief, the determination of the residual acidity of the bentonitecatalyst is conducted in such a way that first an aqueous suspensionwith a certain amount of bentonite catalyst is prepared. An aqueous NaOHsolution with a defined concentration is then titrated to this aqueousbentonite suspension until the pH value of the bentonite suspensionswitches to the alkaline range (pH>7.0), which represents to theend-point of the titration. The pH value is determinedpotentiometrically by means of a previously calibrated KCl-pH electrode(potentiometric indication). Then, the amount of NaOH that was necessaryto reach the end-point of the titration (in milligrams) per gram of thebentonite catalyst applied in the aqueous suspension is calculated. Thiscalculated value corresponds to the residual acidity in mg KOH/gbentonite.

Typically, the amount of free moisture in the bentonite catalyst appliedin step b) of the instant process is at most 30% by weight, preferablyat most 25% by weight, more preferably at most 20% by weight.

The amount of free moisture in the treated bentonite is determined byweighing the individual bentonite against an anhydrous sample of thesame bentonite. The anhydrous sample is obtained by drying in a vacuumoven at a temperature in the range of 100 to 200° C., optionally underreduced pressure of below 200 mbar, preferably at a temperature in therange of 100 to 150° C. and under reduced pressure of below 10 mbar, inparticular of below 1 mbar, until constant weight.

In this more preferred embodiment, the amount of bentonite catalystapplied in step b) of the process according to the present invention isin the range of from 1 to 750 g per mol of the unsaturated alkanol ofthe general formula III.a or III.b applied in step b).

Preferably, the amount of bentonite catalyst applied in step b) is inthe range of from 5 to 500 g per mol of the compound III.a or III.b.,more preferably in the range of from 10 to 250 g per mol of the compoundIII.a or III.b., even more preferably in the range of from 15 to 200 gper mol of the compound III.a or III.b, in particular in the range offrom 20 to 150 g per mol of the compound III.a or III.b applied in stepb).

Typically, the weight ratio of the bentonite catalyst to the compound(II) applied in step b) is in the range of from 0.01:1 to 2.5:1,preferably in the range of from 0.03:1 to 1.3:1, more preferably in therange of from 0.04:1 to 1:1 in particular in the range of from 0.05:1 to0.7:1.

The porous structure of bentonite can further be altered by means ofhydration and dehydration processes, as it is the case with heatactivation, for example (L. A. Shah et al. Applied Clay Science, 2018,162, 155-164).

In a particular preferred embodiment of the present invention, thebentonite catalyst is subjected to a drying step before its use in stepb).

The drying step is usually carried out at a temperature in the range offrom 50 to 200° C., preferably in the range of from 70 to 170° C., inparticular in the range of from 80 to 150° C., especially in the rangeof from 100 to 120° C.

The drying step can generally be performed at ambient pressure or atreduced pressure. It is preferable that the drying step is carried outat reduced pressure.

Specifically, drying step is carried out at a pressure in the range offrom 0.1 to 500 mbar, more specifically in the range of from 1 to 200mbar.

The drying time of the bentonite catalyst depends on the temperature andpressure applied in the drying step and can, thus, vary over a broadrange. Typically, the drying time of the treated bentonite catalyst isin the range of from several minutes to several days but is preferablyin the range of from 30 minutes to 2 days.

The reaction in step b) is usually carried out at a temperature in therange of from 50 to 200° C., preferably in the range of from 70 to 170°C., in particular in the range from 80 to 150° C.

The reaction in step b) can generally be carried out at ambient pressureor at elevated or at reduced pressure.

The reaction in step b) can take place in the absence of or in thepresence of an inert gas. The expression “inert gas”, as used herein,generally means a gas, which under the prevailing reaction conditionsdoes not enter into any reactions with the starting materials, reagents,or solvents participating in the reaction, or with the resultantproducts. It is preferable that the reaction in step b) takes place inthe presence of an inert gas, preferably in the presence of argon ornitrogen, in particular in the presence of nitrogen.

The reaction in step b) is typically carried out in the presence of anorganic solvent.

Preferably, the solvent applied in step b) of the present invention isselected from at least one polar aprotic solvent (PS) as well as fromsolvent mixtures, consisting of at least one polar aprotic solvent (PS)and at least one apolar hydrocarbon solvent (HS), as defined above.

Suitable polar aprotic solvents (PS) are for example selected from thefollowing groups:

-   PS.1 organic carbonates, i.e. linear and cyclic carbonates, such as    for example ethylene carbonate (243° C.), propylene carbonate,    butylene carbonate, 2,3-propylene carbonate, isobutylene carbonate,    dimethyl carbonate (90° C.), diethyl carbonate (128° C.) and    di-n-propyl carbonate;-   PS.2 ketones, such as for example diethylketone (102° C.) or    methylisobutylketone (116° C.);-   PS.3 lactones, such as for example y-butyrolactone (204-206° C.);-   PS.4 lactams, such as for example N-methyl-2-pyrrolidone (NMP, 203°    C.);-   PS.5 nitrils, such as for example acetonitril (82° C.) and    valeronitril (117° C.);-   PS.6 nitro compounds, such as for example nitromethan (101° C.);-   PS.7 tertiary carboxamides, such as for example dimethylformamide    (153° C.);-   PS.8 urea derivatives, such as for example tetramethylurea (177° C.)    and dimethylpropyleneurea (DMPU, 247° C.);-   PS.9 sulfoxides, such as for example dimethylsulfoxide (DMSO, 189°    C.);-   PS.10 sulfones, such as for example sulfolane (285° C.)-   PS.11 alicyclic ethers, such as for example 1,4-dioxane (101° C.);-   PS.12 glycol ethers, such as for example alkylene glycol dialkyl    ethers, dialkylene glycol dialkyl ethers and polyalkylene glycol    dialkyl ethers;

and mixtures thereof.

Amongst these groups, those polar aprotic solvents (PS) are preferredwhich have a boiling point of at least 100° C., more preferably of atleast 120° C., in particular of at least 140° C.

More preferably, the polar aprotic solvent (PS) is selected from thegroups PS.1, PS.3, PS.4, PS.7, PS.8, PS.9, PS.10 and PS.12, even morepreferably from PS.1, PS.7, PS.8 and PS.12, even more preferably fromPS.1 and PS.12, in particular from PS.1.

Specifically, the polar aprotic solvent (PS) is selected from cyclic andlinear carbonates of the general formula V.a and V.b, as defined above.

Preferably, the apolar hydrocarbon solvent (HS) is selected from thegroups HS.1 and HS.2.

More preferably, the apolar hydrocarbon solvent (HS) is selected fromhexane, cyclohexane, heptane, octane and nonane, more specifically fromheptane and octane.

In a preferred embodiment of the present invention, step b) is carriedout in a solvent mixture consisting of at least one polar aproticsolvent (PS), as defined above, and at least one apolar hydrocarbonsolvent (HS), as defined above.

In this preferred embodiment, the content of the PS in the solventmixture is typically in the range of from 35 to 99% by weight,preferably in the range of from 50 to 99% by weight, in particular inthe range of from 50 to 90% by weight, based on the total weight of thesolvent mixture.

Accordingly, the weight ratio of the PS to HS applied in step b) istypically in the range of from 1:3 to 100:1, preferably in the range offrom 1:1 to 100:1, in particular in the range of from 1:1 to 10:1.

In this preferred embodiment, polar aprotic solvents (PS) are preferred,which are not or only sparingly miscible with the at least one apolarhydrocarbon solvent (HS), which means that step b) is carried out in abiphasic solvent mixture consisting of a PS-phase and a HS-phase. Inthis connection, the term “sparingly miscible” means that less than 5%by weight, preferably less than 2% by weight, more preferably less than1% by weight, in particular less than 0.5% by weight, of the polaraprotic solvent (PS) is present in the HS-phase.

In this more preferred embodiment, solvent mixtures are preferredconsisting of at least one polar aprotic solvent of the group PS.1 andat least one apolar hydrocarbon solvent of the group HS.1.

In particular, in this preferred embodiment, the solvent mixtureconsists of at least one polar aprotic solvent (PS), selected fromethylene carbonate, propylene carbonate, butylene carbonate,2,3-propylene carbonate, isobutylene carbonate, diethyl carbonate anddi-n-propyl carbonate, and at least one apolar hydrocarbon solvent (HS),selected from heptane and octane.

In a specific embodiment of the present invention, step b) is carriedout in at least one polar aprotic solvent (PS), as defined above.

The compounds of the general formulae (II) applied in step b) are highlysoluble in the polar aprotic solvent (PS-phase), whereas the apolarreaction product obtained in step b), i.e. the alkylation orcondensation product, which typically separates from the polar aproticsolvent as soon as the reaction mixture is cooled, is highly soluble inthe apolar hydrocarbon solvent (HS-phase). Thus, the use of the abovementioned solvent mixtures has the advantage that the reaction mixtureobtained in step b) can easily be separated by phase separation into aPS-phase, comprising the majority or essentially all of the unreactedcompound (II) as well as the bentonite catalyst, and a HS-phase,comprising the majority or essentially all of the apolar reactionproduct obtained in step b). If necessary, the separation of the apolarreaction product obtained in step b) from the PS-phase can be completedby extraction with the apolar hydrocarbon solvent (HS). The separatedPS-phase can then be returned into the reaction in step b) or reusedlater in another reaction in step b). The separated HS-phase can bedirectly subjected to the next process step or to a purification step.Furthermore, the water formed during the reaction in step b) can easilybe distilled off from the PS-phase allowing an easy recycling of thepolar aprotic solvent (PS). In addition, the use of an apolarhydrocarbon solvent (HS) allows an efficient distillative removal of thewater formed during the reaction in step b) through the formation of anazeotropic mixture.

The concentration of the compound (II) in the polar organic solvent (PS)is typically in the range of from 2 to 50% by weight, preferably in therange of from 3 to 45% by weight, in particular in the range of from 5to 40% by weight.

The molar ratio of the compound (II) to the compound III.a or III.bapplied in step b) is typically in the range of from 1:1 to 10:1,preferably in the range of from 1.05:1 to 5:1, more preferably in therange of from 1.05:1 to 3:1, in particular in the range of from 1.1:1 to2:1.

The compounds of the general formula III.a and III.b are eithercommercially available or can be prepared from readily availableprecursors by processes described in the art, or can be obtained fromnatural sources.

For example the compounds III.a and III.b, wherein Y is hydroxyl arereadily commercially available or can be obtained from natural sources.Compounds III.a and III.b, wherein Y represents a leaving groupdifferent from hydroxyl, as defined above, can be produced from thecorresponding alcohol precursors via conventional nucleophilicsubstitution reactions. These nucleophilic reactions can be performedunder conventional reaction conditions that are well known to theskilled person.

Typically, the reaction in step b) of the process of the presentinvention first proceeds under formation of the Friedel-Craftsalkylation product. In case the hydroxyl groups adjacent to thealkylation position are unprotected, the Friedel-Crafts alkylationreaction is typically accompanied by a following ring-closing reaction(intramolecular hydroxyalkylation of the double bond) to form acondensed six-membered cycle containing an oxygen atom. If desired, theintermediate Friedel-Crafts alkylation product can also be isolated andthe ring-closing reaction can be performed in a separate step. However,it is preferable that the Friedel-Crafts-alkylation and the ring-closingreaction are performed in a single step.

In a preferred embodiment of the present invention, the reaction in stepb) is performed with distillative removal of at least one portion of thewater formed during the reaction. As already mentioned above, thedistillative removal of the water formed during the reaction can befacilitated by using an apolar hydrocarbon solvent (HS), such ascyclohexane, heptane, octane or toluene, in addition to the polaraprotic solvent (PS) in step b), since apolar hydrocarbon solvents (HS)often form azeotropic mixtures with water. To this end, a vapor isremoved from the reaction system and is condensed. In case the vaporconsists of an azeotropic mixture of water with the organic solventapplied in step b) and/or another component of the reaction mixture ofstep b), or the water comprises significant amounts of product orstarting material, the resultant condensate is typically subjected tophase separation to give an aqueous phase and an organic phase. Forthis, the condensate is typically passed into a phase separator(decanter) where mechanical settling causes it to break down into twophases which can be extracted separately. If necessary, a waterimmiscible organic solvent, preferably the organic solvent applied instep b), is added to the condensate before passing the condensate into aphase separator. The aqueous phase is removed and discarded and theorganic phase is at least to some extent returned to the reactionsystem. “Return to the reaction system” means that the organic phase ispassed into any desired at least one reactor of the reaction system.

Any of the suitable condensers can be used for the condensation orpartial condensation of the vapor. These can be cooled by any desiredcoolants. Preference is given to condensers with air cooling and/orwater cooling, particular preference being given here to air cooling.

The reaction in step b) can be performed either in batch wise(discontinuous mode), as described above, or continuous mode. Preferenceis given to performing the reaction in step b) in continuous mode.

If the reaction in step b) is conducted in the batch wise(discontinuous) mode, the reactants and the catalyst are typicallyplaced in a suitable reaction vessel, e.g. a stirred vessel or loopreactor, at the temperatures indicated above until the desiredconversion is reached. The reaction time can be 0.5 to 30 hours,preferably 1 to 20 hours, depending on the amount of catalyst added.

Preferably, the reaction in step b) is conducted in such a way thatfirst the organic solvent and the bentonite catalyst, preferably theacidic heterogeneous catalyst, in particular the treated bentonitecatalyst, are placed into a suitable reaction vessel, e.g. a stirredvessel or loop reactor, and heated to reaction temperature. Optionally,the resulting suspension is kept at reaction temperature for severalminutes, e.g. for 1, 2, 5, 10, 15 or 20 minutes before the suspension iscooled to below 80° C. During these pretreatment steps, an inert gas,preferably argon or nitrogen, is introduced into the apparatus to ensurethat the apparatus is oxygen-free. Afterwards, compound (II) is added inone portion to the preheated solvent/catalyst suspension and theresulting mixture is heated to reaction temperature. Following this, thecompound III.a or III.b is added to the reaction mixture, optionallydissolved in an apolar hydrocarbon solvent (HS). Typically, the compoundIII.a or III.b is added stepwise to the reaction mixture, comprising theorganic solvent, the bentonite catalyst and the compound (II), inseveral portions, e.g. in 2, 3, 4, 5, 10, 15 or 20 portions, or ismetered in continuously. Preferably, the compound III.a or III.b ismetered in continuously. The addition rate of the compound III.a orIII.b to the reaction mixture is typically in the range of from 0.2 to5% by volume/min, preferably in the range of from 0.3 to 3% byvolume/min, in particular in the range of from 0.5 to 2% by volume/min,based on the total volume of the compound III.a or III.b.

Depending on whether a polar aprotic solvent (PS) alone or a mixtureconsisting of a polar aprotic solvent (PS) and an apolar hydrocarbonsolvent (HS) is applied as the organic solvent in step b), the desiredreaction product is separated from the obtained reaction mixture byphase separation and/or by extraction with an apolar hydrocarbon solvent(HS). In this way, two phases are obtained, i.e. a PS-phase, comprisingmainly the bentonite catalyst and eventually unreacted compound (II),and a HS-phase, comprising mainly the desired reaction product andeventually unreacted compound III.a or III.b. After phase separationand/or extraction, the reaction product can be purified bychromatographic methods, distillation and/or crystallization, preferablyby distillation, or the reaction product can be directly subjected tothe next reaction step b).

In a preferred embodiment of the present invention, the bentonitecatalyst, in particular the treated bentonite catalyst, applied in stepb) of the instant process separated from the reaction mixture or thePS-phase after completion of the reaction and reused in a furtherreaction in step b).

For the separation of the bentonite catalyst, in particular the treatedbentonite catalyst, from the reaction mixture or the PS-phase, generallyall processes known to the skilled person that are suitable to separatesolids from liquid mixtures can be used. Preferably, the bentonitecatalyst is removed from the obtained reaction mixture by filtration.After separation, the bentonite catalyst, in particular the treatedbentonite catalyst, is dried in an inert gas stream, preferably in anitrogen stream. The drying time of the bentonite catalyst, inparticular the treated bentonite catalyst, in the inert gas stream canvary over a broad range, depending on the nature of the solvent appliedin the reaction in step b). The drying time of the bentonite catalyst inthe inert gas stream is typically in the range of from a few minutes toseveral days, i.e. from 5 minutes to 5 days. The drying time of thebentonite catalyst in the inert gas stream can for example be 10minutes, 30 minutes 1 hour, 5 hours, 12 hours, 1 day, 3 days or 5 days.

In another preferred embodiment of the present invention, the PS-phase,comprising mainly the bentonite catalyst and eventually unreactedcompound (II), which is obtained after phase separation and/orextraction of the reaction mixture obtained in step b) with an apolarhydrocarbon solvent (HS), is directly reused in a further reaction instep b).

The reaction in step b) can be performed either in batch wise orcontinuous mode. Preference is given to performing the reaction in stepb) in continuous mode.

The continuous reaction is generally carried out in at least onereactor, e.g. 1, 2, 3, 4 or 5 reactors, preferably in one reactor,comprising the treated bentonite catalyst in the form of a fixed bed ormoving bed, preferably in the form of a fixed bed, into which, forexample, a mixture of the organic solvent with the compound and thecompound III.a or III.b are fed. In the preferred fixed-bed operationmode, the reactor can be operated in sump operation mode, i.e. thereaction mixture is guided from bottom to top, or in the trickleoperation mode, i.e. the reaction mixture will be guided through thereactor from top to bottom. The water formed during the reaction isremoved by drawing off a vapor from the top of the reactor, which iscondensed and separated into an organic phase, eventually comprising theapolar hydrocarbon solvent (HS) and minor amounts of unreacted compoundand/or reaction product, and a water phase, as described above. Theorganic phase is optionally returned to the at least one reactor. Astream of the reaction mixture, comprising the polar aprotic solvent(PS), the apolar hydrocarbon solvent (HS), if present, the reactionproduct and eventually non-reacted compound II is drawn off from thebottom of the reactor. Depending on whether a polar aprotic solvent (PS)alone or a mixture consisting of a polar aprotic solvent (PS) and anapolar hydrocarbon solvent (HS) is used as the organic solvent in stepb), the desired reaction product is separated from the obtained reactionmixture by phase separation and/or by extraction with an apolarhydrocarbon solvent (HS). The reaction product can then be purified orthe reaction product can be directly subjected to the next reactionstep.

The catalyst hourly space velocity in the reaction in step b) ispreferably in the range from 0.1 to 50 kg of compound III.a or III.b perkg of catalyst and hour, in particular in the range of from 0.2 to 30 kgof compound III.a or III.b per kg of catalyst and hour.

The at least one reactor may be selected from any desired reactors whichare suitable for carrying out heterogeneously catalyzed chemicalreactions in liquid phase.

Suitable reactors are non-back-mixed reactors, such as tubular reactorsor dwell-time containers provided with internals, but preferablyback-mixed reactors such as stirred-tank reactors or loop reactors.However, it is also possible to use combinations of successiveback-mixed reactors and non-back-mixed reactors.

Optionally, several reactors can also be combined in a multistageapparatus. Such reactors are, for example, loop reactors withincorporated sieve trays, cascaded containers, tubular reactors withinterim feed point or stirred columns.

Step c):

In step c) of the instant process, the condensation product obtained instep b) is reacted with a C₂-C₇-carboxylic acid or with aC₂-C₇-carboxylic acid anhydride in the presence of bentonite catalyst.

According to the invention, the reaction in step c) is conducted in thepresence of a bentonite catalyst.

Suitable and preferred bentonite catalysts that can be applied in stepc) of the instant process are as defined above.

In a preferred embodiment of the present invention, step c) is conductedin the presence of the same bentonite catalyst as applied in step b).

Preferably, in this preferred embodiment, the bentonite catalyst used insteps b) and c) is separated from the reaction mixture after completionof the reaction in step c) and reused in a further reaction in step b).The recycling of the bentonite catalysts is performed as describe abovefor step b).

In a more preferred embodiment of the present invention, theesterification reaction in step c) is performed in the presence of atreated bentonite catalyst, in particular in the presence of an acidtreated bentonite catalyst, as defined above.

In a particularly preferred embodiment of the present invention steps b)and c) are conducted in the presence of a carbonate solvent, as definedabove.

In another particular embodiment of the present invention, the reactionin steps b) and c) are conducted in the presence of a carbonatesolvent/apolar hydrocarbon solvent mixture, as described above.

Suitable and preferable carbonate solvents as well as suitable andpreferable apolar hydrocarbon solvents (HS), if present, are as definedabove.

Even more preferably, in this special embodiment, step c) is carried outin the same carbonate solvent and, if present, in the same apolarhydrocarbon solvents (HS), as applied in step b).

In particular, the reaction mixture obtained in step b) is used directlyin the reaction in step c), i.e. step b) and step c) are performed as aone-pot reaction.

The reaction product, i.e. the compound of formula (I), obtained in stepc) can be worked up in a conventional way, e.g. by filtering off thebentonite catalyst; by adding an apolar hydrocarbon solvent (HS), ifnecessary; separating the phases; and, where appropriate, purifying thecrude products by using chromatographic methods, by distillation, ifapplicable, or by recrystallization.

In a special embodiment of the present invention, steps a.2), b) and c)are carried out in the same carbonate solvent and, if present, in thesame apolar hydrocarbon solvent (HS). Preferably, in this specialembodiment, the reaction mixture obtained in step a.2) is directly usedin the reaction in step b), after removal of the hydrogenation catalyst,and the reaction mixture obtained in the subsequent step b) is directlyused in the reaction in step c).

The process of the present invention provides the compounds (I) in highyields and selectivity. Typically, the compounds (I) are furtherpurified by recrystallization, distillation, if applicable, or by usingchromatographic methods.

Generally, only minor amounts of by-products are obtained.

Common by-products that are obtained by using processes described in theprior art for the preparation of compounds of the general formula (I),are for example diene compounds of the general formula X.1 to X.3, whichare formed from compounds III.a or III.b via unwanted eliminationreactions, as can be depicted from scheme 4.

wherein

-   X is as defined above and-   X-2 is preferably selected from moieties of formulae X-2.a and X-2.b

-   -   wherein    -   n is an integer of from 0 to 2 and    -   * indicates the attachment point to the rest of the molecule.

The formation of these diene by products is typically increased whencarboxylic acids, such as oxalic acid, tartaric acid or citric acid, areapplied as condensation catalysts. These acids are capable of formingester intermediates with the compounds III.a or III.b., which can easilyeliminate to the compounds of the general formula X.1 to X.3.

The diene compounds of the general formula X.1 to X.3 can also reactwith the compounds (II) in step b). However, the reaction is very slowcompared to the reaction with compounds III.a or III.b. The formation ofthe diene compounds X.1 to X.3 should thus be avoided.

Furthermore, benzofurane isomers of formula XI-1 can be formed from thereaction of the hydroquinone compounds (II) with compounds III.a, asdepicted in scheme 5, which are difficult to separate from the desiredcondensation product.

By using the process of the present invention, the formation of thesecommon side products can successfully be suppressed.

The examples below provide further explanation of the invention. Theseexamples are not to be understood as restricting the invention.

EXAMPLES Abbreviations

GC stands for gas chromatography,

-   HPLC high performance liquid chromatography,-   TMH stands for trimethylhydroquinone (2,3,5-trimethylhydroquinone),-   TMQ stands for trimethylquinone (2,3,5-trimethylquinone),-   PC propylene carbonate-   EC ethylene carbonate

1. Analytics:

1.1 Determination of product purity:

The purity of the products was determined by Gas Chromatography area-%.The yield of the compounds I and II was determined via GC-weight-% usingdocosan as internal standard and n-heptane as solvent.

GC-System: Agilent 6980N;

GC-Column: Agilent DB-1: 30 m (length), 0.25 mm (inner diameter), 0.25micrometer (film-thickness);

Temperature program: 80° C. to 350° C. at 10°/min, 350° C. for 10minutes, total runtime: 37 minutes.

The amount of compounds (Ill) in the (final) reaction mixture wasdetermined via HPLC-weight-%:

HPLC-System: Agilent Series 1200

HPLC-column: Zorbax Eclipse PAH, 1.8 μm, 50*4.6 mm von Agilent®

Eluent:

A: water with 0.1 vol-% H₃PO₄;

B: Acetonitril

Time [min.] % B 0.0 5 3.0 15 10.0 100 17.0 100 17.1 5

Detector: UV-detector k=210 nm, BW=5 nm, flow-rate: 1.2 mL/min,injection: 2 μL, Temperature: 60° C., run-time: 20 min., pressure: about130 bar

1.2 Determination of the BET Surface Area:

System: Quantachrome Autosorb Automated Gas Sorption System 6B,serial-#: 10896010901;

Software: Autosorb for Windows® for AS-3 and AS-6 Version 1.22;

Sample weight: 0.28-0.43 g of solid catalyst (e.g. treated bentonitecatalyst);

Bath temperature: 77.4 K;

Run time: 64-106.7 min;

Gas for measuring: nitrogen; Purity of gas: nitrogen 5.0;

Drying before measuring: via rotary vane pump and finallyturbo-molecular pump for 16 hours at 120° C., <1 mbar;

System Parameters: Cross-Sec Area 16.2 Å/molec;

Multipoint BET: 5 points p/p_(o); 0.05≤p/p_(o)≤0.30.

1.3 Determination of the residual acidity of the solid catalyst (mgKOH/g solid catalyst):

The determination of the residual acidity of the solid catalyst (e.g.treated bentonite catalyst) is conducted in such a way that first anaqueous suspension with a certain amount of the solid catalyst isprepared as follows: 1.0 g to 1.5 g of the solid catalyst is suspendedin 50 mL of deionized water and stirred for 1 h. A previously calibratedKCl-pH-electrode is placed into this suspension. An aqueous NaOHsolution with a defined concentration of 0.1 mol/L is then titrated tothis aqueous suspension until the pH value of the suspension of thesolid catalyst switches to the alkaline range (inflection point), whichrepresents the end-point of the titration. The volume V1 in mL of NaOHsolution used to reach the inflection point is recorded.

Furthermore, a blank determination is carried out in the same way using50 mL of deionized water. The volume V2 in mL of NaOH solution used isrecorded.

The residual acidity of the solid catalyst sample (in mg KOH/g solidcatalyst), which is determined as total acid value, is then calculatedbased on the following formula:

${{Residual}\mspace{14mu}{acidity}} = \frac{5{6.1}\frac{g}{mol}*\left( {{V1} - {V2}} \right)*c*t}{m1}$

-   56.1 g/mol represents a constant (molar mass of KOH in g/mol);-   m1 is the mass, in grams, of the test portion, i.e. the solid    catalyst sample;-   V1 is the volume, in milliliters, of NaOH solution used to    neutralize the catalyst suspension (volume until inflection point is    reached);-   V2 is the volume, in milliliters, of NaOH solution used in the blank    determination (volume until inflection point is reached−usually no    volume consumed/blank is typically zero);-   C is the concentration, in moles per liter, of the NaOH solution;-   t is the titer of the NaOH solution.

The determination of the residual acidity is repeated once and thusdetermined twice.

1.4 Determination of the Density of the Catalyst:

Machine: Pycnometer series AccuPyc II 1340

Company: Micromeritics

Inert gas: Helium

Sample weight: 2.1-4.8 g

Sample chamber: 10 mL

Program “analysis conditions” was used including 99 cycles and eachcycle with 5 repetitions.

The samples were treated for 16 h at 120° C., <1 mbar vacuum beforemeasuring.

Density [g/ccm]=mass of sample [g]/volume of sample [ccm]

1. Preparation Examples Origin and Specification of the Applied AcidTreated Bentonite Catalysts:

The acid treated bentonites that are used as catalysts in the followingpreparation examples are either acid treated bentonites from the companyBASF SE that were developed in-house (BASF SE internal material) or acidtreated Bentonites available from Sigma Aldrich or from the companyClariant Produkte GmbH.

Bentonite catalysts with the following specifications were applied:

Residual Surface Water Catalyst acidity area (BET) content *) He-densityNo.: Source: [mg KOH/g] [m²/g] [wt %] [g/ccm] 1 BASF SE 30-36 215-23512-16 2.57 ± 0.1 2 BASF SE 24-30 215-235 18-22 2.57 ± 0.1 3 BASF SE26-32 300-320 11-15 2.45 ± 0.1 4 BASF SE 21-27 230-250 10-14 2.57 ± 0.15 BASF SE 16-22 275-295 11-15 2.56 ± 0.1 6 Clariant 18-24 145-165 10-142.39 ± 0.1 Produkte GmbH 7 Clariant 11-17 265-285  9-13 2.46 ± 0.1Produkte GmbH 8 Clariant 13-19 285-305 10-14 2.45 ± 0.1 Produkte GmbH 9Clariant <1 175-195  8-12 2.46 ± 0.1 Produkte GmbH *) determined byKarl-Fischer-Titration and/or by weight loss on drying (16 h at 120° C.and at a pressure of < 1 mbar).

For the preparation of the acid treated bentonite catalysts from thecompany BASF SE (catalysts 1 to 5) Aberdeen clay, which is known for itshigh quality, was used as the natural bentonite starting material. Thesebentonites are activated using sulfuric acid followed by conversion tothe final granular mineral catalysts.

General Reaction Procedure and Remarks:

The reaction progress is monitored via thin layer chromatography and GC.

Step 1: Reduction of TMQ to TMH

Step 2: Friedel-Crafts-Alkylation and condensation

Unless otherwise noted all reactions are performed in a glass flaskusing a blade agitator and a dean stark trap, which,

-   -   in case a mixture of HS and PS is used as the solvent, is filled        with the HS employed,    -   in case a PS is used as the solvent that forms no azeotrope with        water, is left empty, and    -   in case a solvent is used that forms an azeotrope with water, is        filled with the solvent employed (unlike water) that is        azeotropically removed with water.

Step 3: Esterification

2.1 Preparation of 2,3,5-trimethylhydroquinone (Step 1)

4 g 2,3,5-trimethylquinone (99.6%, 26.5 mmol) is dissolved in 76 g (63.1mL) propylene carbonate at room temperature. 0.4 g palladium on charcoal(10%, 0.38 mmol, 0.01 eq) is added and the resulting reaction mixture ishydrogenated for 23 h at a hydrogen pressure of 8 bar and at 64° C.After a reaction time of 6 h the filtered reaction mixture is only aslightly yellowish solution, after a reaction time of 23 h a colorlesssolution. The following GC analysis is obtained:

Reaction time GC-area-% [h] TMH TMQ 6 97.5 2.3 23 98.9 0.9

2.2 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 1 and 2) Preparation of2,3,5-trimethylhydroquinone

14 g 2,3,5-trimethylquinone (99.6%, 92.85 mmol) is dissolved in 79.3 g(65.9 mL) propylene carbonate at room temperature. 2.8 g palladium oncharcoal (10%, 2.6 mmol, 0.03 eq) is added and the resulting reactionmixture is hydrogenated for 23 h at a hydrogen pressure of 8 bar and 88°C. Then, the reaction mixture is filtered immediately and 83.3 g of analmost colorless eluate (97.6 GC-a % TMH and 0.05 GC-a % TMQ) isobtained.

Preparation of all Racemic Alpha-Tocopherol (Catalyst 2)

Towards the crude TMH in propylene carbonate (81.4 g after analytics,assumption: 100% yield: 92.85 mmol, 1.7 eq) 0.19 g catalyst 2 (driedover night at 120° C./50 mbar in the vacuum drying oven)/g TMH (2.7 gcatalyst 2) is added. The reaction mixture is brought to 120-125° C. andstirred for 15 min. Then, 16.45 g isophytol (97.4%, 54 mmol) iscontinuously added to the reaction mixture over a period of 2 h(temperature of the reaction mixture: 120-125° C.) while the waterformed during the reaction is removed by distillation. After a furtherreaction time of 4 h at 125° C., at room temperature overnight, andfurther 4 h at 125° C. the reaction mixture is brought to roomtemperature, 20 mL of heptane is added, it was further stirred for 15min and then filtered over celite to remove the catalyst 2. The filtercake is washed with 6*20 mL heptane and 3*20 mL propylene carbonate.After phase separation, the propylene carbonate phase is extracted with4*25 mL heptane. The combined heptane phases are dried over sodiumsulfate. The solvent is removed under reduced pressure 50° C./5 mbarplus 15 min oil pump vacuum. 24.09 g of crude alpha-tocopherol (91.6GC-area % and 85.66 GC-weight %) is obtained as a dark red, clear,viscous residue in 89% yield (based on GC-weight % over two steps). Eachstep has an average yield of 94.5% yield.

2.3 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2/H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 1)

233.57 g (193.99 mL) propylene carbonate and 0.22 g catalyst 1 (dried at120° C. overnight, 50 mbar)/g TMH (21.75 g catalyst 1) are heated undera nitrogen gas stream to 120-125° C. and stirred for 15 min. Thesuspension is then cooled to <90° C. and 100.11 g (652.5 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120-125° C. Then, 136.35 g (162.13 mL) isophytol (447.9 mmol,97.4% purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 120-125° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 6 h at 120-125° C. the reaction mixture iscooled to room temperature. The mixture is filtered over a glass suctionfilter D4 loaded with celite to remove the catalyst 1. The filter cakeis washed with 6*130 mL heptane and 3*130 mL propylene carbonate. Allmother liquors and washing liquors are collected and joined. The phasesof the eluate are separated. The propylene carbonate phase is extractedwith 4*190 mL heptane. The combined heptane phases are dried over sodiumsulfate and the volatiles are removed under reduced pressure at 50-55°C./5 mbar plus 15 min oil pump vacuum: 200 g of crude alpha-tocopherol(94.6 GC-area-% and 94.53 GC-weight-%) is obtained as dark red, clear,viscous residue. This corresponds to a yield of 98%.

2.4 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 1)

138.08 g (141.91 mL) diethyl carbonate and 0.22 g catalyst 1 (dried at120° C. overnight, 50 mbar)/g TMH (7.5 g catalyst 1) are heated under anitrogen gas stream to 120-123° C. and stirred for 15 min. Thesuspension is then cooled to <90° C. and 34.52 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120-125° C. Then, 45.76 g (54.41 mL) isophytol (150 mmol,97.2% purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 124-119° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 6 h at 120-125° C. the reaction mixture iscooled to room temperature. 45 mL of heptane is added to the reactionmixture which is stirred for 15 min at room temperature. Then, themixture is filtered over a glass suction filter D4 loaded with celite toremove the catalyst 1. The filter cake is washed with 6*45 mL heptane.All mother liquors and washing liquors are collected and joined. Theeluate from which precipitation is observed is subsequently filtered andthe solvent is removed under reduced pressure at 50-55° C./5 mbar plus15 min oil pump vacuum: 68.84 g of crude alpha-tocopherol (84.8GC-area-% and 78.79 GC-weight-%) is obtained as red-brown, viscous andcloudy residue. This corresponds to a yield of 84%.

2.5 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 1)

80.55 g (71.92 mL) gamma-butyrolactone and 0.22 g catalyst 1 (dried at120° C. overnight, 50 mbar)/g TMH (7.5 g catalyst 1) are heated under anitrogen gas stream to 120-125° C. and stirred for 15 min. Thesuspension is then cooled to <90° C. and 34.52 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120-125° C. Then, 45.76 g (54.3 mL) isophytol (150 mmol, 97.4%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 120-125° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 6 h at 120-125° C. the reaction mixture iscooled to room temperature. 45 mL of heptane is added to the reactionmixture which is stirred for 15 min at room temperature. Then, themixture is filtered over a glass suction filter D4 loaded with celite toremove the catalyst 1. The filter cake is washed with 6*45 mL heptaneand 3*45 mL gamma-butyrolactone. All mother liquors and washing liquorsare collected and joined. The phases of the eluate are separated. Thegamma-butyrolactone phase is extracted with 4*65 mL heptane. Thecombined heptane phases are dried over sodium sulfate and the volatilesare removed under reduced pressure at 50-55° C./5 mbar plus 15 min oilpump vacuum: 68.71 g of crude alpha-tocopherol (89.7 GC-area-% and 78.38GC-weight-%) is obtained as dark red, clear, viscous residue. Thiscorresponds to a yield of 83%.

2.6 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 1)

This reaction was performed without water removal and thus a Dean starktrap. The apparatus used consists of a flask, blade agitator and refluxcondenser.

80.55 g (66.9 mL) propylene carbonate and 0.22 g catalyst 1 (dried at120° C. overnight, 50 mbar)/g TMH (7.5 g catalyst 1) are heated under anitrogen gas stream to 120-125° C. and stirred for 15 min. Thesuspension is then cooled to <90° C. and 34.52 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120-125° C. Then, 45.86 g (54.5 mL) isophytol (150 mmol, 97%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 120-125° C.). Aftera further reaction time of 4 h at 123-124° C., at room temperatureovernight, and further 2 h at 124° C. the reaction mixture is cooled toroom temperature. 45 mL of heptane is added to the reaction mixturewhich is stirred for 15 min at room temperature. Then, the mixture isfiltered over a glass suction filter D4 loaded with celite to remove thecatalyst 1. The filter cake is washed with 6*45 mL heptane and 3*45 mLpropylene carbonate. All mother liquors and washing liquors arecollected and joined. The phases of the eluate are separated. Thepropylene carbonate phase is extracted with 4*65 mL heptane. Thecombined heptane phases are dried over sodium sulfate and the volatilesare removed under reduced pressure at 50-55° C./5 mbar plus 15 min oilpump vacuum: 66.04 g of crude alpha-tocopherol (92.7 GC-area-% and 84.55GC-weight-%) is obtained as dark red, clear, viscous residue. Thiscorresponds to a yield of 86%.

2.7 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2HLchromen-6-ol (all Racemic Alpha-Tocopherol) (Step 2; Catalyst 2)

103.14 g (78.08 mL) ethylene carbonate, 47.73 g (67.9 mL) n-octane (plus60 mL octane in dean-stark-trap) and 0.65 g catalyst 2 (dried at 120° C.overnight, 50 mbar)/g TMH (22.5 g catalyst 2) are heated under anitrogen gas stream to slight n-octane reflux (temperature of thereaction mixture: 120-125° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.38 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120° C.

Then, 45.39 g (53.97 mL) isophytol (150 mmol, 98% purity, 1 eq) iscontinuously added to the reaction mixture over a period of 2 h(temperature of the reaction mixture: 120-125° C.) while the waterformed during the reaction is removed by distillation. After a furtherreaction time of 6 h at 123-126° C. the reaction mixture is cooled to<60° C. and 50 g of propylene carbonate is added. Then, the reactionmixture is further cooled to room temperature and filtered over a glasssuction filter D4 loaded with celite to remove the catalyst 2. Thefilter cake is washed with 3*45 mL octane and 3*45 mL propylenecarbonate. All mother liquors and washing liquors are collected andjoined. The phases of the eluate are separated. The ethylene/propylenecarbonate phase is extracted with 4*65 mL octane. The combined octanephases are dried over sodium sulfate and the volatiles are removed underreduced pressure at 50-55° C./5 mbar plus 15 min oil pump vacuum: 63.66g of crude alpha-tocopherol (95.5 GC-area-% and 91.44 GC-weight-%) isobtained as dark red, clear, viscous residue. This corresponds to ayield of 90%.

2.8 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 2)

232.63 g (193.21 mL) propylene carbonate, 118.06 g (167.9 mL) n-octane(plus 60 mL octane in dean-stark-trap) and 0.22 g catalyst 2 (dried at120° C. overnight, 50 mbar)/g TMH (21.75 g catalyst 2) are heated undera nitrogen gas stream to slight n-octane reflux (temperature of thereaction mixture: 120-125° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 99.7 g (625.5 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 123° C. Then, 137.22 g (163.17 mL) isophytol (435 mmol, 94%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 125-123° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 4 h at 123-125° C., at room temperatureovernight, and further 2 h at 125° C. the reaction mixture is cooled toroom temperature and filtered over a glass suction filter D4 loaded withcelite to remove the catalyst 2. The filter cake is washed with 3*130 mLheptane and 3*130 mL propylene carbonate. All mother liquors and washingliquors are collected and joined. The phases of the eluate areseparated. The propylene carbonate phase is extracted with 4*190 mLheptane. The combined heptane/n-octane phases are dried over sodiumsulfate and the volatiles are removed under reduced pressure at 50-55°C./5 mbar plus 15 min oil pump vacuum: 199.16 g of crudealpha-tocopherol (92.6 GC-area-% and 87.57 GC-weight-%) is obtained asdark red, clear, viscous residue. This corresponds to a yield of 93%.

2.9 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2/H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 2)

80.55 g (66.9 mL) propylene carbonate and 0.22 g catalyst 2 (dried at120° C. overnight, 50 mbar)/g TMH (7.5 g catalyst 2) are heated to50-90° C. and 34.52 g (225 mmol) trimethylhydroquinone (1.5 eq) isadded. The mixture is then heated to 150° C. and 45.67 g (54.3 mL)isophytol (150 mmol, 97.4% purity, 1 eq) is continuously added to thereaction mixture over a period of 2 h. After a further reaction time of6 h the reaction mixture is cooled to room temperature. 45 mL of heptaneis added to the reaction mixture which is stirred for 15 min at roomtemperature. Then, the mixture is filtered over a glass suction filterD4 loaded with celite to remove the catalyst 2. The filter cake iswashed with 6*45 mL heptane and 3*45 mL propylene carbonate. All motherliquors and washing liquors are collected and joined. The phases of theeluate are separated. The propylene carbonate phase is extracted with4*65 mL heptane. The combined heptane phases are dried over sodiumsulfate and the volatiles are removed under reduced pressure at 50° C./5mbar plus 15 min oil pump vacuum: 65.61 g of crude alpha-tocopherol(92.5 GC-area-% and 84.73 GC-weight-%) is obtained as dark red, clear,viscous residue. This corresponds to a yield of 86%.

2.10 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 2)

80.55 g (66.9 mL) propylene carbonate and 0.33 g catalyst 2 (dried at120° C. overnight, 50 mbar)/g TMH (11.25 g catalyst 2) are heated undera nitrogen gas stream to 120-125° C. and stirred for 15 min. Thesuspension is then cooled to <90° C. and 34.52 g (225 mmol)trimethylhydroquinone (3 eq) is added. The mixture is then again heatedto 120-125° C. Then, 22.88 g (27.21 mL) isophytol (75 mmol, 97.2%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 1 h (temperature of the reaction mixture: 121-125° C.). Aftera further reaction time of 6 h at 120-125° C. the reaction mixture iscooled to room temperature. 45 mL of heptane is added to the reactionmixture which is stirred for 15 min at room temperature. Then, themixture is filtered over a glass suction filter D4 loaded with celite toremove the catalyst 2. The filter cake is washed with 6*45 mL heptaneand 3*45 mL propylene carbonate. All mother liquors and washing liquorsare collected and joined. The phases of the eluate are separated. Thepropylene carbonate phase is extracted with 4*65 mL heptane. Thecombined heptane phases are dried over sodium sulfate and the volatilesare removed under reduced pressure at 50° C./5 mbar plus 15 min oil pumpvacuum: 33.99 g of crude alpha-tocopherol (95.2 GC-area-% and 88.45GC-weight-%) is obtained as dark red, clear, viscous residue. Thiscorresponds to a yield of 93%.

2.11 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 2)

80.55 g (66.9 mL) propylene carbonate, 39.79 g (58.18 mL) n-heptane(plus 60 mL heptane in dean-stark-trap) and 0.22 g catalyst 2 (dried at120° C. overnight, 50 mbar)/g TMH (7.5 g catalyst 2) are heated under anitrogen gas stream to slight n-heptane reflux (temperature of thereaction mixture: 100° C.) and stirred for 15 min under reflux.

The suspension is then cooled to <80° C. and 34.52 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 100° C. Then, 45.86 g (54.52 mL) isophytol (150 mmol, 97%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 100-102° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 6 h at 103-104° C., at room temperatureovernight, and further 2 h at 102° C. the reaction mixture is cooled toroom temperature and filtered over a glass suction filter D4 loaded withcelite to remove the catalyst 2. The filter cake is washed with 3*45 mLheptane and 3*45 mL propylene carbonate. All mother liquors and washingliquors are collected and joined. The phases of the eluate areseparated.

The propylene carbonate phase is extracted with 4*65 mL heptane. Thecombined heptane/n-octane phases are dried over sodium sulfate and thevolatiles are removed under reduced pressure at 50° C./5 mbar plus 15min oil pump vacuum: 63.99 g of crude alpha-tocopherol (88.9 GC-area-%and 85.26 GC-weight-%) is obtained as dark red, clear, viscous residue.This corresponds to a yield of 84%.

2.12 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 3)

80.55 g (66.9 mL) propylene carbonate and 0.22 g catalyst 3 (dried at120° C. overnight, 50 mbar)/g TMH (7.5 g catalyst 3) are heated under anitrogen gas stream to 120-125° C. and stirred for 15 min. Thesuspension is then cooled to <90° C. and 34.52 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120-125° C. Then, 45.86 g (54.52 mL) isophytol (150 mmol, 97%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 122-125° C.). Aftera further reaction time of 4 h at 120-125° C., at room temperature overthe weekend, and further 2 h at 120-125° C. the reaction mixture iscooled to room temperature. 45 mL of heptane is added to the reactionmixture which is stirred for 15 min at room temperature. Then, themixture is filtered over a glass suction filter D4 loaded with celite toremove the catalyst 3. The filter cake is washed with 6*45 mL heptaneand 3*45 mL propylene carbonate. All mother liquors and washing liquorsare collected and joined. The phases of the eluate are separated. Thepropylene carbonate phase is extracted with 4*65 mL heptane. Thecombined heptane phases are dried over sodium sulfate and the volatilesare removed under reduced pressure at 50° C./5 mbar plus 15 min oil pumpvacuum: 65.43 g of crude alpha-tocopherol (94.1 GC-area-% and 87.05GC-weight-%) is obtained as dark red, clear, viscous residue. Thiscorresponds to a yield of 88%.

2.13 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2HLchromen-6-ol (all Racemic Alpha-Tocopherol) (Step 2; Catalyst 4)

80.22 g (66.63 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane(plus 60 mL octane in dean-stark-trap) and 0.65 g catalyst 4 (dried at120° C. overnight, 50 mbar)/g TMH (22.5 g catalyst 4) are heated under anitrogen gas stream to slight n-octane reflux (temperature of thereaction mixture: 120-122° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.38 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120° C. Then, 45.39 g (53.97 mL) isophytol (150 mmol, 98%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 118-120° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 6 h at 121-124° C. the reaction mixture iscooled to room temperature and filtered over a glass suction filter D4loaded with celite to remove the catalyst 4. The filter cake is washedwith 3*45 mL n-octane and 3*45 mL propylene carbonate. All motherliquors and washing liquors are collected and joined. The phases of theeluate are separated. The propylene carbonate phase is extracted with4*65 mL n-octane. The combined n-octane phases are dried over sodiumsulfate and the volatiles are removed under reduced pressure at 55° C./5mbar plus 15 min oil pump vacuum: 64.06 g of crude alpha-tocopherol(90.5 GC-area-% and 86.86 GC-weight-%) is obtained as dark red, clear,viscous residue. This corresponds to a yield of 86%.

2.14 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2HLchromen-6-ol (all Racemic Alpha-Tocopherol) (Step 2; Catalyst 5)

80.22 g (66.63 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane(plus 60 mL octane in dean-stark-trap) and 0.65 g catalyst 5 (dried at120° C. overnight, 50 mbar)/g TMH (22.5 g catalyst 5) are heated under anitrogen gas stream to slight n-octane reflux (temperature of thereaction mixture: 120-121° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.38 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 120° C. Then, 45.39 g (53.97 mL) isophytol (150 mmol, 98%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 115-120° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 4 h at 119-123° C., at room temperature overthe weekend, and further 2 h at 122° C. the reaction mixture is cooledto room temperature and filtered over a glass suction filter D4 loadedwith celite to remove the catalyst 5. The filter cake is washed with3*45 mL n-octane and 3*45 mL propylene carbonate. All mother liquors andwashing liquors are collected and joined. The phases of the eluate areseparated. The propylene carbonate phase is extracted with 4*65 mLn-octane. The combined n-octane phases are dried over sodium sulfate andthe volatiles are removed under reduced pressure at 55° C./5 mbar plus15 min oil pump vacuum: 65.08 g of crude alpha-tocopherol (87.3GC-area-% and 85.15 GC-weight-%) is obtained as dark red, clear, viscousresidue. This corresponds to a yield of 86%.

2.15 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 6)

80.55 g (66.9 mL) propylene carbonate and 0.33 g catalyst 6 (undried)/gTMH (11.25 g catalyst 6) are heated under a nitrogen gas stream to120-125° C. and stirred for 15 min. The suspension is then cooled to<90° C. and 34.52 g (225 mmol) trimethylhydroquinone (1.5 eq) is added.The mixture is then again heated to 120-125° C. Then, 45.67 g (54.3 mL)isophytol (150 mmol, 97.4% purity, 1 eq) is continuously added to thereaction mixture over a period of 1 h (temperature of the reactionmixture: 122-125° C.). After a further reaction time of 6 h at 122-125°C. the reaction mixture is cooled to room temperature. 45 mL of heptaneand celite is added to the reaction mixture which is stirred for 15 minat room temperature. Then, the mixture is filtered over a glass suctionfilter D4 to remove celite and catalyst 6. The filter cake is washedwith 6*45 mL heptane and 3*45 mL propylene carbonate. All mother liquorsand washing liquors are collected and joined. The phases of the eluateare separated. The propylene carbonate phase is extracted with 4*65 mLheptane. The combined heptane phases are dried over sodium sulfate andthe volatiles are removed under reduced pressure at 50° C./5 mbar plus15 min oil pump vacuum: 64.75 g of crude alpha-tocopherol (86.7GC-area-% and 81.19 GC-weight-%) is obtained as dark red, clear, viscousresidue. This corresponds to a yield of 81%.

2.16 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2/H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 7)

80.55 g (66.9 mL) propylene carbonate and 0.33 g catalyst 7 (undried)/gTMH (11.25 g catalyst 7) are heated under a nitrogen gas stream to120-122° C. and stirred for 15 min. The suspension is then cooled to<90° C. and 34.52 g (225 mmol) trimethylhydroquinone (1.5 eq) is added.The mixture is then again heated to 120-125° C. Then, 45.67 g (54.3 mL)isophytol (150 mmol, 97.4% purity, 1 eq) is continuously added to thereaction mixture over a period of 1 h (temperature of the reactionmixture: 120-124° C.). After a further reaction time of 6 h at 120-125°C. the reaction mixture is cooled to room temperature. 45 mL of heptaneis added to the reaction mixture which is stirred for 15 min at roomtemperature. Then, the mixture is filtered over a glass suction filterD4 loaded with celite to remove the catalyst 7. The filter cake iswashed with 6*45 mL heptane and 3*45 mL propylene carbonate. All motherliquors and washing liquors are collected and joined. The phases of theeluate are separated. The propylene carbonate phase is extracted with4*65 mL heptane. The combined heptane phases are dried over sodiumsulfate and the volatiles are removed under reduced pressure at 50° C./5mbar plus 15 min oil pump vacuum: 64.76 g of crude alpha-tocopherol(91.8 GC-area-% and 86.01 GC-weight-%) is obtained as dark red, clear,viscous residue. This corresponds to a yield of 86%.

2.17 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 8)

80.55 g (66.9 mL) propylene carbonate and 0.44 g catalyst 8 (undried)/gTMH (15 g catalyst 8) are heated under a nitrogen gas stream to 120° C.and stirred for 15 min. The suspension is then cooled to <90° C. and34.52 g (225 mmol) trimethylhydroquinone (1.5 eq) is added. The mixtureis then again heated to 120-125° C. Then, 45.67 g (54.3 mL) isophytol(150 mmol, 97.4% purity, 1 eq) is continuously added to the reactionmixture over a period of 2 h (temperature of the reaction mixture:121-125° C.). After a further reaction time of 4 h at 121-125° C., roomtemperature overnight, and further 2 h at 120-125° C. the reactionmixture is cooled to room temperature. 45 mL of heptane is added to thereaction mixture which is stirred for 15 min at room temperature. Then,the mixture is filtered over a glass suction filter D4 loaded withcelite to remove the catalyst 8. The filter cake is washed with 6*45 mLheptane and 4*45 mL propylene carbonate. All mother liquors and washingliquors are collected and joined. The phases of the eluate areseparated. The propylene carbonate phase is extracted with 4*65 mLheptane. The combined heptane phases are dried over sodium sulfate andthe volatiles are removed under reduced pressure at 50° C./5 mbar plus15 min oil pump vacuum: 64.27 g of crude alpha-tocopherol (75.8GC-area-% and 87.13 GC-weight-%) is obtained as dark red, clear, viscousresidue. This corresponds to a yield of 87%.

2.18 Preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2/H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 9)

80.55 g (66.9 mL) propylene carbonate and 0.33 g catalyst 9 (undried)/gTMH (11.25 g catalyst 9) are heated under a nitrogen gas stream to 120°C. and stirred for 15 min. The suspension is then cooled to <90° C. and34.52 g (225 mmol) trimethylhydroquinone (1.5 eq) is added. The mixtureis then again heated to 120-125° C. Then, 45.67 g (54.3 mL) isophytol(150 mmol, 97.4% purity, 1 eq) is continuously added to the reactionmixture over a period of 1 h (temperature of the reaction mixture:123-125° C.). After a further reaction time of 6 h at 125° C. thereaction mixture is analysed: 30 GC-area % TMH, 5 GC-area % phytadienes,19 GC-area % Phytyl-TMH, no alpha-tocopherol. The reaction mixture isdiscarded.

2.19 Continuous preparation of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all Racemic Alpha-Tocopherol) (Step 2; Catalyst 9) Applied Catalyst:

Montmorillonite K10 (pH of 3-4, surface area) “diluted” with Celite in a1:1 mass ratio from the company Thales Nano, packed into a cartridge(so-called CatCart). The employed CatCart-cartridge had a size of 70×4mm and a filling mass of 459 mg.

Continuous Preparation Procedure:

An 8 wt % solution of TMH in bis(2-methoxyethyl)ether (=diglyme) and a10.4 wt % solution of isophytol in bis(2-methoxyethyl)ether (=diglyme)are pumped with a volume flow of 5 mL/h onto the above described CatCartfilled with K10 and Celite and heated to 200° C. The catalyst CatCart isplaced in vertical position.

The reaction progress is monitored via GC: 61.3 GC-area % of2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol(all racemic alpha-tocopherol), 19.4 GC-area % of TMH and 13.5 GC-area %of phytadienes are obtained.

2.20 Preparation of all Racemic Alpha-Tocopherol Acetate (Steps 1, 2 and3) Preparation of 2,3,5-trimethylhydroquinone

14 g 2,3,5-trimethylquinone (99.6%, 92.85 mmol) is dissolved in 79.7 g(66.2 mL) propylene carbonate at room temperature. 2.8 g palladium oncharcoal (10%, 2.63 mmol, 0.03 eq) is added and the resulting reactionmixture is hydrogenated for 22.5 h at a hydrogen pressure of 8 bar andat 87-93° C. The reaction mixture is filtered at temperature and undernitrogen using a warm glass suction filter D4 with a paper filter and84.31 g eluate (95.3 GC-area % trimethylhydroquinone and 0.28 GC-a %trimethylquinone) are obtained.

Preparation of all Racemic Alpha-Tocopherol (Catalyst 2)

Towards the crude trimethylhydroquinone in propylene carbonate obtainedin the first step (82.83 g, 1.73 eq, assumption 100% yield, 92.85 mmol)0.19 g catalyst 2 (dried at 120° C. overnight, 50 mbar)/g TMH (2.69 gcatalyst 2) are added and heated to 120° C. and stirred for 15 min at120-124° C. Then, 16.38 g (19.47 mL) isophytol (53.8 mmol, 97.4% purity,1 eq) is continuously added to the reaction mixture over a period of 2 h(temperature of the reaction mixture: 124-125° C.) while the waterformed during the reaction is removed by distillation. After a furtherreaction time of 5 h at 125° C. the reaction mixture is stirredovernight at room temperature.

Preparation of all Racemic Alpha-Tocopherol Acetate (Catalyst 2)

The brown suspension obtained from the second step is heated to 50° C.and 22.19 g (20.55 mL) acetic anhydride (220 mmol, 4 eq) arecontinuously added over a period of 15 min. Then, the reaction mixtureis heated to 100° C. and stirred for 4 h. After cooling to roomtemperature, 20 mL of heptane is added to the reaction mixture which isstirred for 15 min. Then, the reaction mixture is filtered over a glasssuction filter D4 loaded with celite to remove the catalyst 2. Thefilter cake is washed with 6*20 mL heptane and 3*20 mL propylenecarbonate. All mother liquors and washing liquors are collected andjoined. The phases of the eluate are separated. The propylene carbonatephase is extracted with 4*25 mL heptane. The combined heptane phases aredried over sodium sulfate and the volatiles are removed under reducedpressure at 50° C./5 mbar plus 15 min oil pump vacuum: 25.71 g of crudeall racemic alpha-tocopherol acetate (89.28 GC-area-%) is obtained asbrown, clear, viscous residue. This corresponds to a yield of 90% (basedon GC-area % over 3 steps).

2.21 Preparation of all Racemic Alpha-Tocopherol Acetate (Steps 2 and 3)Preparation of all Racemic Alpha-Tocopherol (Catalyst 2)

100.29 g (83.3 mL) propylene carbonate and 35.15 g catalyst 2 are addedand heated to 120-125° C. and stirred for 15 min. The suspension is thencooled to <90° C. and 22.92 g (150 mmol) trimethylhydroquinone (1.0 eq)is added. The mixture is then again heated to 120° C. Then, 46.75 g(55.59 mL) isophytol (154.5 mmol, 98% purity, 1.03 eq) is continuouslyadded to the reaction mixture over a period of 2 h (temperature of thereaction mixture: 120-123° C.) while the water formed during thereaction is removed by distillation. After a further reaction time of 4h at 123-124° C. the reaction mixture is stirred over the weekend atroom temperature.

Preparation of all Racemic Alpha-Tocopherol Acetate (Catalyst 2)

Towards the brown suspension obtained from the previous step 30.94 g(28.64 mL) acetic anhydride (300 mmol, 2 eq) are continuously added overa period of 10 min.

Then, the reaction mixture is reactively distilled for 2 h (500 mbar,inner temperature 87-92° C., transition temperature 28-33° C., oil bathtemperature 100° C.). Then, the reaction mixture is brought to roomtemperature and 45 mL of heptane is added and the reaction mixture isstirred for 15 min. Then, it is filtered over a glass suction filter D4to remove the catalyst 2. The filter cake is washed with 3*45 mL heptaneand 3*45 mL propylene carbonate. All mother liquors and washing liquorsare collected and joined. The phases of the eluate are separated. Thepropylene carbonate phase is extracted with 4*65 mL heptane. Thecombined heptane phases are dried over sodium sulfate and the volatilesare removed under reduced pressure at 50° C./5 mbar plus 15 min oil pumpvacuum: 71.79 g of crude all racemic alpha-tocopherol acetate (88.08GC-area-%) is obtained as brown, clear, viscous residue containing 0.18GC-area % alpha-tocopherol. This corresponds to a yield of 89% (based onGC-area % over 2 steps).

2.22 Effect of the Drying Temperature of the Bentonite Catalyst

The effect of drying the bentonite catalyst prior to its use in thecondensation reaction of TMH with IP was evaluated. Two reactions wereconducted in analogy to example 2.8, except that 225 mmol TMH wereapplied here instead of 625.5 mmol TMH (the amounts of the otherreactants were adapted accordingly). The results are summarized in table1.

TABLE 1 Influence of the drying temperature of the bentonite catalyst 2on alpha-tocopherol yield Drying temperature alpha-tocopherol ExampleNo: Entry: catalyst 2 [° C.] yield [%] 2.22.1. 1 undried 79 2.22.2. 2 6082 2.22.3. 3 100 88 2.22.4 4 120 93

In the bentonite catalyzed reaction of TMH with IP, the drying of thebentonite catalyst prior to its use can improve the catalyst turnoverunder the reaction conditions applied here (e.g. the applied PC/octanesolvent mixture).

The yield of alpha-tocopherol increases with increasing dryingtemperature of the bentonite catalyst 2 from 79% (undried catalyst 2) to93% (catalyst 2 dried at 120° C., 50 mbar, vacuum drying oven,overnight).

Example 2.22.1 Preparation of all Racemic Alpha-Tocopherol

80.22 g (66.6 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane (plus60 mL octane in dean-stark-trap) and 0.74 g catalyst 2 (undried as itis)/g TMH (25.43 g catalyst 2) are heated under a nitrogen gas stream toslight reflux (temperature of the reaction mixture: 109° C.) and stirredfor 15 min under reflux. The suspension is then cooled to <80° C. and34.38 g (225 mmol) trimethylhydroquinone (1.5 eq) is added. The mixtureis then again heated to slight reflux at 113° C. Then, 45.39 g (53.97mL) isophytol (150 mmol, 98% purity, 1 eq) is continuously added to thereaction mixture over a period of 2 h (temperature of the reactionmixture: 113-112° C.) while the water formed during the reaction isremoved by distillation. After a further reaction time of 6 h at118-123° C. the reaction mixture is cooled to room temperature andfiltered over a glass suction filter D4 loaded with celite to remove thecatalyst 2. The filter cake is washed with 3*45 mL n-octane and 3*45 mLpropylene carbonate. All mother liquors and washing liquors arecollected and joined. The phases of the eluate are separated. Thepropylene carbonate phase is extracted with 4*65 mL n-octane. Thecombined n-octane phases are dried over sodium sulfate and the volatilesare removed under reduced pressure at 55° C./5 mbar plus 15 min oil pumpvacuum: 59.31 g of crude alpha-tocopherol (89.7 GC-area-% and 85.47GC-weight-%) is obtained as dark red, clear, viscous residue. Thiscorresponds to a yield of 79%.

Example 2.22.2 Preparation of all Racemic Alpha-Tocopherol

80.22 g (66.6 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane (plus60 mL octane in dean-stark-trap) and 0.65 g catalyst 2 (dried at 60° C.,overnight, 50 mbar)/g TMH (22.5 g catalyst 2) are heated under anitrogen gas stream to slight reflux (temperature of the reactionmixture: 115-117° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.38 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to slight reflux at 118° C. Then, 45.39 g (53.97 mL) isophytol(150 mmol, 98% purity, 1 eq) is continuously added to the reactionmixture over a period of 2 h (temperature of the reaction mixture:119-117° C.) while the water formed during the reaction is removed bydistillation. After a further reaction time of 6 h at 120-124° C. thereaction mixture is cooled to room temperature and filtered over a glasssuction filter D4 loaded with celite to remove the catalyst 2. Thefilter cake is washed with 3*45 mL n-octane and 3*45 mL propylenecarbonate. All mother liquors and washing liquors are collected andjoined. The phases of the eluate are separated. The propylene carbonatephase is extracted with 4*65 mL n-octane. The combined n-octane phasesare dried over sodium sulfate and the volatiles are removed underreduced pressure at 55° C./5 mbar plus 15 min oil pump vacuum: 61.10 gof crude alpha-tocopherol (91.1 GC-area-% and 86.31 GC-weight-%) isobtained as dark red, clear, viscous residue. This corresponds to ayield of 82%.

Example 2.22.3 Preparation of all Racemic Alpha-Tocopherol

80.22 g (66.6 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane (plus60 mL octane in dean-stark-trap) and 0.65 g catalyst 2 (dried at 100°C., overnight, 50 mbar)/g TMH (22.5 g catalyst 2) are heated under anitrogen gas stream to slight reflux (temperature of the reactionmixture: 120-121° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.38 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to slight reflux at 122° C. Then, 45.39 g (53.97 mL) isophytol(150 mmol, 98% purity, 1 eq) is continuously added to the reactionmixture over a period of 2 h (temperature of the reaction mixture:122-121° C.) while the water formed during the reaction is removed bydistillation. After a further reaction time of 6 h at 123-125° C. thereaction mixture is cooled to room temperature and filtered over a glasssuction filter D4 loaded with celite to remove the catalyst 2. Thefilter cake is washed with 3*45 mL n-octane and 3*45 mL propylenecarbonate. All mother liquors and washing liquors are collected andjoined. The phases of the eluate are separated. The propylene carbonatephase is extracted with 4*65 mL n-octane. The combined n-octane phasesare dried over sodium sulfate and the volatiles are removed underreduced pressure at 55° C./5 mbar plus 15 min oil pump vacuum: 65.91 gof crude alpha-tocopherol (92.1 GC-area-% and 86.47 GC-weight-%) isobtained as dark red, clear, viscous residue. This corresponds to ayield of 88%.

Example 2.22.4 Preparation of all Racemic Alpha-Tocopherol

80.22 g (66.6 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane (plus60 mL octane in dean-stark-trap) and 0.65 g catalyst 2 (dried at 120°C., overnight, 50 mbar)/g TMH (22.5 g catalyst 2) are heated under anitrogen gas stream to slight reflux (temperature of the reactionmixture: 120-121° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.38 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to slight reflux at 121° C. Then, 45.39 g (53.97 mL) isophytol(150 mmol, 98% purity, 1 eq) is continuously added to the reactionmixture over a period of 2 h (temperature of the reaction mixture:115-121° C.) while the water formed during the reaction is removed bydistillation. After a further reaction time of 6 h at 118-123° C. thereaction mixture is cooled to room temperature and filtered over a glasssuction filter D4 loaded with celite to remove the catalyst 2. Thefilter cake is washed with 3*45 mL n-octane and 3*45 mL propylenecarbonate. All mother liquors and washing liquors are collected andjoined. The phases of the eluate are separated. The propylene carbonatephase is extracted with 4*65 mL n-octane. The combined n-octane phasesare dried over sodium sulfate and the volatiles are removed underreduced pressure at 55° C./5 mbar plus 15 min oil pump vacuum: 68.47 gof crude alpha-tocopherol (91.2 GC-area-% and 87.93 GC-weight-%) isobtained as dark red, clear, viscous residue. This corresponds to ayield of 93%.

2.23 Recycling of the Bentonite Catalyst in Step 2

The possibility to recycle the bentonite catalyst applied in theFriedel-Crafts-alkylation and condensation reaction was evaluated.Several reactions were conducted as described below (example 2.23.1), inwhich the bentonite catalyst 2 was recovered in each reaction and reusedin the following identical reaction.

The recycling of the bentonite catalyst 2 was shown fivefold for theFriedel-Crafts-alkylation and condensation reaction under otherwiseidentical conditions (see examples 2.23.1. to 2.23.6. in Table 2). Theyield can be reproduced within the scope of the error.

TABLE 2 Recycling of the bentonite catalyst 2 alpha-Tocopherol ExampleNo: Entry: yield [%] 2.23.1. 1 86 2.23.2. 2 87 2.23.3. 3 89 2.23.4. 4 872.23.5. 5 90 2.23.6. 6 89

Example 2.23.1 Preparation of all Racemic Alpha-Tocopherol

80.22 g (66.63 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane(plus 60 mL octane in dean-stark-trap) and 0.65 g catalyst 2 (dried at120° C., overnight, 50 mbar)/g TMH (22.5 g catalyst 2) are heated undera nitrogen gas stream to slight n-octane reflux (temperature of thereaction mixture: 120-121° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.38 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 121° C. Then, 45.39 g (53.97 mL) isophytol (150 mmol, 98%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 116-121° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 4 h at 120-122° C., at room temperatureovernight, and further 2 h at 122° C. the reaction mixture is cooled toroom temperature and filtered over a glass suction filter D4 to removethe catalyst 2. The filter cake is washed with 3*45 mL n-octane and 3*45mL propylene carbonate. The residue is sucked to dryness and furtherdried in a stream of nitrogen overnight (moist weight: 40.20 g, dryweight: 38.11 g). The thus recycled bentonite catalyst 2 is againapplied in example 2.23.2.

All mother liquors and washing liquors are collected and joined. Thephases of the eluate are separated. The propylene carbonate phase isextracted with 4*65 mL n-octane. The combined n-octane phases are driedover sodium sulfate and the volatiles are removed under reduced pressureat 55° C./5 mbar plus 15 min oil pump vacuum: 64.90 g of crudealpha-tocopherol (92.0 GC-area-% and 86.02 GC-weight-%) is obtained asred, clear, viscous residue. This corresponds to a yield of 86%.

Example 2.23.2 Preparation of all Racemic Alpha-Tocopherol

80.22 g (66.63 mL) propylene carbonate, 40.71 g (57.91 mL) n-octane(plus 60 mL octane in dean-stark-trap) and 38.11 g catalyst 2 fromexample 2.23.1. are heated under a nitrogen gas stream to slightn-octane reflux (temperature of the reaction mixture: 120-124° C.) andstirred for 15 min under reflux. The suspension is then cooled to <80°C. and 34.38 g (225 mmol) trimethylhydroquinone (1.5 eq) is added. Themixture is then again heated to 122° C. Then, 45.39 g (53.97 mL)isophytol (150 mmol, 98% purity, 1 eq) is continuously added to thereaction mixture over a period of 2 h (temperature of the reactionmixture: 119-122° C.) while the water formed during the reaction isremoved by distillation. After a further reaction time of 2 h at 122°C., at room temperature overnight, and further 4 h at 123-124° C. thereaction mixture is cooled to room temperature and filtered over a glasssuction filter D4 to remove the catalyst 2. The filter cake is washedwith 3*45 mL n-octane and 3*45 mL propylene carbonate. The residue issucked to dryness and further dried in a stream of nitrogen over theweekend (dry weight: 33.33 g). The thus recycled bentonite catalyst 2 isagain applied in example 2.23.3.

All mother liquors and washing liquors are collected and joined. Thephases of the eluate are separated. The propylene carbonate phase isextracted with 4*65 mL heptane. The combined heptane/n-octane phases aredried over sodium sulfate and the volatiles are removed under reducedpressure at 55° C./5 mbar plus 15 min oil pump vacuum: 65.62 g of crudealpha-tocopherol (92.6 GC-area-% and 86.04 GC-weight-%) is obtained asred, clear, viscous residue. This corresponds to a yield of 87%.

Examples 2.23.3-2.23.6 are performed as described in Example 2.23.2.

2.24 Recycling of the Bentonite Catalyst in Step 2 and 3 Example 2.24.1Preparation of all Racemic Alpha-Tocopherol

100.29 g (83.3 mL) propylene carbonate and 1.01 g catalyst 2 (dried at120° C., overnight, 50 mbar)/g TMH (23.17 g catalyst 2) are added andheated to 123-124° C. and stirred for 15 min. The suspension is thencooled to <90° C. and 22.92 g (150 mmol) trimethylhydroquinone (1.0 eq)is added. The mixture is then again heated to 120° C. Then, 46.75 g(55.59 mL) isophytol (154.5 mmol, 98% purity, 1.03 eq) is continuouslyadded to the reaction mixture over a period of 2 h (temperature of thereaction mixture: 120-121° C.) while the water formed during thereaction is removed by distillation. After a further reaction time of 4h at 120-125° C. the reaction mixture is stirred overnight at roomtemperature.

Preparation of all Racemic Alpha-Tocopherol Acetate

Towards the brown suspension obtained from the previous step 30.94 g(28.64 mL) acetic anhydride (300 mmol, 2 eq) are continuously added overa period of 10 min. Then, the reaction mixture is reactively distilledfor 1 h (310-335 mbar, inner temperature 74-88° C., transitiontemperature 28-45° C., oil bath temperature 100° C.). The reactionmixture is stirred at room temperature under normal pressure over theweekend. Then, the reaction mixture is further reactively distilled for1 h (310-335 mbar, inner temperature 64-67° C., transition temperature32-34° C., oil bath temperature 75° C.). Then, the reaction mixture isbrought to room temperature and 45 mL of heptane is added and thereaction mixture is stirred for 15 min. Then, it is filtered over aglass suction filter D4 to remove the catalyst 2. The filter cake iswashed with 3*45 mL heptane and 3*45 mL propylene carbonate. The residueis sucked to dryness and further dried in a stream of nitrogen for 3days (moist weight: 42.76 g, dry weight: 35.15 g). The thus recycledbentonite catalyst 2 is again applied in example 2.24.2.

All mother liquors and washing liquors are collected and joined. Thephases of the eluate are separated. The propylene carbonate phase isextracted with 4*65 mL heptane. The combined heptane phases are driedover sodium sulfate and the volatiles are removed under reduced pressureat 50° C./5 mbar plus 15 min oil pump vacuum: 68.80 g of crude allracemic alpha-tocopherol acetate (79.90 GC-area-%) is obtained asocher-yellow, clear, viscous residue containing 8.34 GC-area %alpha-tocopherol. This corresponds to a yield of 78% (based on GC-area %over 2 steps).

Example 2.24.2 Preparation of all Racemic Alpha-Tocopherol

100.29 g (83.3 mL) propylene carbonate and 35.15 g catalyst 2 fromexample 2.24.1 are added and heated to 120-125° C. and stirred for 15min. The suspension is then cooled to <90° C. and 22.92 g (150 mmol)trimethylhydroquinone (1.0 eq) is added. The mixture is then againheated to 120° C. Then, 46.75 g (55.59 mL) isophytol (154.5 mmol, 98%purity, 1.03 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 120-123° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 4 h at 123-124° C. the reaction mixture isstirred over the weekend at room temperature.

Preparation of all Racemic Alpha-Tocopherol Acetate

Towards the brown suspension obtained from the previous step 30.94 g(28.64 mL) acetic anhydride (300 mmol, 2 eq) are continuously added overa period of 10 min. Then, the reaction mixture is reactively distilledfor 2 h (500 mbar, inner temperature 87-92° C., transition temperature28-33° C., oil bath temperature 100° C.). Then, the reaction mixture isbrought to room temperature and 45 mL of heptane is added and thereaction mixture is stirred for 15 min. Then, it is filtered over aglass suction filter D4 to remove the catalyst 2. The filter cake iswashed with 3*45 mL heptane and 3*45 mL propylene carbonate. All motherliquors and washing liquors are collected and joined. The phases of theeluate are separated. The propylene carbonate phase is extracted with4*65 mL heptane. The combined heptane phases are dried over sodiumsulfate and the volatiles are removed under reduced pressure at 50° C./5mbar plus 15 min oil pump vacuum: 71.79 g of crude all racemicalpha-tocopherol acetate (88.08 GC-area-%) is obtained as brown, clear,viscous residue containing 0.18 GC-area % alpha-tocopherol. Thiscorresponds to a yield of 89% (based on GC-area % over 2 steps).

2.25 Recycling of the TMH Used in Excess in the Carbonate Solvent

The possibility to recycle the non-reacted, excess TMH together with thecarbonate solvent applied in the Friedel-Crafts-alkylation andcondensation reaction was evaluated. Two reactions were conducted inanalogy to example 2.8, except that 225 mmol TMH were applied hereinstead of 625.5 mmol TMH (the amounts of the other reactants wereadapted accordingly) and that the non-reacted excess TMH is recovered inthe carbonate solvent after completion of the reaction and reused in thefollowing identical reaction. In both reactions the obtained yields wereidentical (examples 2.25.1 and 2.25.2 below, 87% yield in each case).Thus, the non-reacted, excess TMH can be successfully recycled togetherwith carbonate solvent.

Example 2.25.1 Preparation of all Racemic Alpha-Tocopherol

80.55 g (66.9 mL) propylene carbonate, 40.9 g (58.18 mL) n-octane (plus60 mL octane in dean-stark-trap) and 0.22 g catalyst 2 (dried at 120°C., overnight, 50 mbar)/g TMH (7.5 g catalyst 2) are heated under anitrogen gas stream to slight n-octane reflux (temperature of thereaction mixture: 120-125° C.) and stirred for 15 min under reflux. Thesuspension is then cooled to <80° C. and 34.52 g (225 mmol)trimethylhydroquinone (1.5 eq) is added. The mixture is then againheated to 121° C. Then, 45.86 g (54.52 mL) isophytol (150 mmol, 97%purity, 1 eq) is continuously added to the reaction mixture over aperiod of 2 h (temperature of the reaction mixture: 120-125° C.) whilethe water formed during the reaction is removed by distillation. After afurther reaction time of 4 h at 124-125° C., at room temperatureovernight, and further 2 h at 125° C. the reaction mixture is cooled toroom temperature and filtered over a glass suction filter D4 loaded withcelite to remove the catalyst 2. The filter cake is washed with 3*45 mLn-octane and 3*45 mL propylene carbonate. All mother liquors and washingliquors are collected and joined. The phases of the eluate areseparated. The propylene carbonate phase is extracted with 4*65 mLn-octane. The combined n-octane phases are dried over sodium sulfate andthe volatiles are removed under reduced pressure at 55° C./5 mbar plus15 min oil pump vacuum: 64.58 g of crude alpha-tocopherol (93.1GC-area-% and 87.24 GC-weight-%) is obtained as dark red, clear, viscousresidue. This corresponds to a yield of 87%. Furthermore, 172.31 g of ared clear propylene carbonate phase containing 93.6 GC-area-%, 6.2HPLC-weight-% of unreacted TMH is obtained. This corresponds to arecovery of 93% TMH (70 mmol of 75 mmol of TMH used in excess). 85.87 gof this propylene carbonate phase is recycled in 2.25.2.

alpha-tocopherol TMH GC GC GC HPLC area-% weight-% area-% weight-% Rawalpha-tocopherol 93.1 87.24 0 — Propylene carbonate phase 0.2 — 93.6 6.2

Example 2.25.2 Preparation of all Racemic Alpha-Tocopherol

85.87 g of propylene carbonate phase from 2.25.1 (containing 5.32 g,34.96 mmol, 0.23 eq TMH), 40.9 g (58.18 mL) n-octane (plus 60 mL octanein dean-stark-trap) and 0.22 g catalyst 2 (dried at 120° C., overnight,50 mbar)/g TMH (7.5 g catalyst 2) are heated under a nitrogen gas streamto slight n-octane reflux (temperature of the reaction mixture: 120-123°C.) and stirred for 15 min under reflux. The suspension is then cooledto <80° C. and 29.16 g (190.04 mmol) trimethylhydroquinone (1.23 eq; intotal: 1.46 eq) is added. The mixture is then again heated to 120° C.Then, 47.2 g (56.12 mL) isophytol (154.4 mmol, 97% purity, 1 eq) iscontinuously added to the reaction mixture over a period of 2 h(temperature of the reaction mixture: 120-125° C.) while the waterformed during the reaction is removed by distillation. After a furtherreaction time of 4 h at 124-125° C., at room temperature overnight, andfurther 2 h at 125° C. the reaction mixture is cooled to roomtemperature and filtered over a glass suction filter D4 loaded withcelite to remove the catalyst 2. The filter cake is washed with 3*45 mLn-octane and 3*45 mL propylene carbonate. All mother liquors and washingliquors are collected and joined. The phases of the eluate areseparated. The propylene carbonate phase is extracted with 4*65 mLn-octane. The combined n-octane phases are dried over sodium sulfate andthe volatiles are removed under reduced pressure at 55° C./5 mbar plus15 min oil pump vacuum: 65.70 g of crude alpha-tocopherol (92.9GC-area-% and 87.71 GC-weight-%) is obtained as dark red, clear, viscousresidue. This corresponds to a yield of 87%. Furthermore, 196.85 g of ared clear propylene carbonate phase containing 91.5 GC-area-%, 5.5HPLC-weight-% of unreacted TMH is obtained. This corresponds to arecovery of >99% TMH (71 mmol of 71 mmol of TMH used in excess).

alpha-tocopherol TMH GC GC GC HPLC area-% weight-% area-% weight-% Rawalpha-tocopherol 92.9 87.71 0 — Propylene carbonate phase 0.2 — 91.5 5.5

1.-17. (canceled)
 18. Process for preparing a compound of the generalformula I

wherein R¹, R² and R³ independently of each other are selected fromhydrogen and methyl, R⁴ is selected from C₁-C₆-alkyl, and X is selectedfrom C₁-C₂₀-alkyl and C₂-C₂₀-alkenyl, comprising the following steps: a)providing a hydroquinone compound of the general formula II,

wherein R¹, R² and R³ are as defined above, b) reacting the hydroquinonecompound II provided in step a) with an unsaturated compound of thegeneral formula III.a or III.b

wherein X is as defined above, Y is selected from OH, halogen, —O—R¹¹,—S—R¹² and —SO₂—R¹², R¹¹ is selected from C₁-C₄-alkyl, C₁-C₄-alkanoyland trifluoroacetyl, and R¹² is selected from C₁-C₆-alkyl,trifluoromethyl and phenyl, where phenyl is unsubstituted or substitutedwith 1, 2, 3, 4 or 5 radicals selected from halogen and methyl, in thepresence of a bentonite catalyst, and c) reacting the condensationproduct obtained in step b) with a C₂-C₇-carboxylic acid or with aC₂-C₇-carboxylic acid anhydride in the presence of a bentonite catalyst.19. The process according to claim 18, where steps b) and c) areperformed in the presence of the same bentonite catalyst.
 20. Theprocess according to claim 18, where the bentonite catalyst used insteps b) and c) is subjected to an acid treatment prior to its use insteps b) and c).
 21. The process according to claim 20, where thebentonite catalyst used in steps b) and c) is additionally subjected toa drying step before its use in step b) and c).
 22. The processaccording to claim 18, where the bentonite catalyst has a BET surfacearea in the range of from 100 to 600 m²/g.
 23. The process according toclaim 18, where the bentonite catalyst has a residual acidity, measuredas mg KOH/g bentonite by titration with potentiometric indication, inthe range of from 5 to
 50. 24. The process according to claim 18, wherethe amount of free moisture in the bentonite catalyst is at most 25% byweight.
 25. The process according to claim 18, where the weight ratio ofthe bentonite catalyst to the hydroquinone compound (II) applied in stepb) is in the range of from 0.1:1 to 1.5:1.
 26. The process according toclaim 18, where the bentonite catalyst used in steps b) and c) isseparated from the reaction mixture after completion of the reaction instep c) and reused in a further reaction in step b).
 27. The processaccording to claim 18, where steps b) and c) are conducted in thepresence of a polar aprotic solvent.
 28. The process according to claim27, where step c) is carried out in the polar aprotic solvent used instep b).
 29. The process according to claim 27, where the polar aproticsolvent is selected from at least one organic carbonate and frommixtures, consisting of at least one apolar organic carbonate and atleast one hydrocarbon compound.
 30. The process according to claim 18,where the reaction mixture obtained in step b) is used directly in thereaction in step c).
 31. The process according to claim 18, wherein thecompounds of the general formula I and II R¹, R² and R³ are methyl andR⁴ if present, is selected from methyl.
 32. The process according toclaim 18, where X is methyl or has one of the following meanings X-1 toX-6

wherein * indicates the attachment point to the chromane ring.
 33. Theprocess according to claim 18, where the provision of the hydroquinonecompound II in step a) comprises the following steps: a.1) providing aquinone compound of the general formula IV,

wherein R¹, R² and R³, independently of each other, are hydrogen ormethyl, a.2) catalytic hydrogenation of the quinone compound of formulaIV provided in step a.1) in the presence of hydrogen and a hydrogenationcatalyst.
 34. The process according to claim 33, where step a.2) iscarried out in a carbonate solvent.
 35. The process according to claim18, where the bentonite catalyst has a BET surface area in the range offrom 150 to 400 m²/g.
 36. The process according to claim 18, where thebentonite catalyst has a residual acidity, measured as mg KOH/gbentonite by titration with potentiometric indication, in the range offrom 10 to
 40. 37. The process according to claim 18, where the amountof free moisture in the bentonite catalyst is at most 20% by weight.